The c.188A>G (p.Tyr63Cys) variant in PTPN11 (NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys)) has been reported in the literature in at least 6 unrelated individuals and has been found to segregate with clinical features of a RASopathy in at least 15 family members (PS4, PP1_Strong; PMID: 16498234, 12634870, 12325025, 11704759). In-vitro functional studies provide some evidence that the p.Tyr63Cys variant may impact protein function (PS3; PMID: 22711529). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Tyr63Cys variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied: PP1_Strong, PS4, PS3, PM1, PP2, PP3 (Version 2.1; 09/17/2024).
NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys)
Germline
Reviewed by expert panel
Help
Reviewed by expert panel. Learn more about how ClinVar calculates review status.
Pathogenic
for
Noonan syndrome
Classification is based on the expert panel submission
Sep 2024 by
ClinGen RASopathy Variant Curation Expert Panel
Help
FDA Recognized Database
The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Somatic
Clinical impact
Help
criteria provided, single submitter. Learn more about how ClinVar calculates review status.
This classification is based on the single submission received
Help
The aggregate somatic clinical impact for this variant for one or more tumor types, using the AMP/ASCO/CAP terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
1
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys)
Variation ID: 13333 Accession: VCV000013333.118
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q24.13 12: 112450368 (GRCh38) [ NCBI UCSC ] 12: 112888172 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Jul 27, 2026 Sep 17, 2024 Somatic - Clinical impact Nov 22, 2025 Nov 22, 2025 Sep 27, 2022 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002834.5:c.188A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002825.3:p.Tyr63Cys missense NM_001330437.1:c.188A>G NM_001330437.2:c.188A>G NP_001317366.1:p.Tyr63Cys missense NM_001374625.1:c.185A>G NP_001361554.1:p.Tyr62Cys missense NM_080601.3:c.188A>G NP_542168.1:p.Tyr63Cys missense NC_000012.12:g.112450368A>G NC_000012.11:g.112888172A>G NG_007459.1:g.36637A>G LRG_614:g.36637A>G LRG_614t1:c.188A>G Q06124:p.Tyr63Cys - Protein change
- Y63C, Y62C
- Other names
-
NM_002834.4(PTPN11):c.188A>G
NM_002834.5(PTPN11):c.188A>G
- Canonical SPDI
- NC_000012.12:112450367:A:G
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| PTPN11 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1365 | 1379 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (22) |
criteria provided, multiple submitters, no conflicts
|
Dec 5, 2025 | RCV000014261.66 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 24, 2026 | RCV000033468.28 | |
| Pathogenic (16) |
criteria provided, multiple submitters, no conflicts
|
Oct 1, 2025 | RCV000077857.75 | |
| Pathogenic (4) |
reviewed by expert panel
|
Sep 17, 2024 | RCV000157000.25 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 18, 2017 | RCV000515408.13 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 2, 2016 | RCV000588678.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 26, 2017 | RCV000722014.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 10, 2018 | RCV001249667.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 14, 2020 | RCV001813198.11 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 6, 2022 | RCV003137518.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 14, 2021 | RCV003147286.8 | |
|
PTPN11-related disorder
|
Pathogenic (2) |
criteria provided, single submitter
|
- | RCV004528109.2 |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 16, 2024 | RCV005251036.1 | |
|
Monogenic short stature
|
Pathogenic (1) |
criteria provided, single submitter
|
Feb 12, 2024 | RCV006629056.1 |
| click to load more conditions click to collapse | ||||
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
Expand all rows
Collapse all rows
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Sep 17, 2024)
C
Contributing to aggregate classification
|
reviewed by expert panel
|
Noonan syndrome
(Autosomal dominant inheritance)
|
ClinGen RASopathy Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV000616372.4 First in ClinVar: Dec 19, 2017 Last updated: Oct 13, 2024 |
Comment:
show
The c.188A>G (p.Tyr63Cys) variant in PTPN11 (NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys)) has been reported in the literature in at least 6 unrelated individuals and has been found to segregate with clinical features of a RASopathy in at least 15 family members (PS4, PP1_Strong; PMID: 16498234, 12634870, 12325025, 11704759). In-vitro functional studies provide some evidence that the p.Tyr63Cys variant may impact protein function (PS3; PMID: 22711529). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Tyr63Cys variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied: PP1_Strong, PS4, PS3, PM1, PP2, PP3 (Version 2.1; 09/17/2024). (less)
Observation: 1
Collection method: curation
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: curation
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Jan 26, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Noonan syndrome 1 |
Clinical Genetics Laboratory, Region Ostergotland
Accession: SCV001984986.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Jun 02, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226875.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 8
|
|
|
Pathogenic
(Mar 18, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Revvity Omics, Revvity
Accession: SCV003826749.3
First in ClinVar: Mar 04, 2023 Last updated: Sep 06, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Aug 18, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Noonan syndrome 1 |
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV002768758.3
First in ClinVar: Dec 24, 2022 Last updated: Dec 01, 2025 |
Comment:
show
This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes); The variant has strong previous evidence of pathogenicity in unrelated individuals with Noonan syndrome. It is a 3-star pathogenic variant in ClinVar (reviewed by the ClinGen RASopathy Variant Curation Expert Panel), and is reported in the literature in individuals with Noonan syndrome (PMIDs: 11704759; 12325025; 12634870); The variant has strong evidence for segregation with disease in multiple families (PMID: 12325025; 12634870); Variant is located in a hotspot region or cluster of pathogenic variants (N-SH2 domain; DECIPHER); Missense variant consistently predicted to be damaging by multiple in silico tools and is highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from tyrosine to cysteine; This variant is heterozygous; This gene is known to be associated with autosomal dominant disease; Both loss of function and gain of function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250), and Noonan syndrome with multiple lentigines have been associated with loss of function variants, whereas Noonan syndrome 1 (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 24935154, 21533187); Variants in this gene are known to have variable expressivity (PMID: 20301303); This variant has been shown to be maternally inherited by trio analysis. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Jan 24, 2026)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
RASopathy |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000253879.15
First in ClinVar: Oct 11, 2015 Last updated: Feb 15, 2026 |
Comment:
show
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 63 of the PTPN11 protein (p.Tyr63Cys). This variant is present in population databases (rs121918459, gnomAD 0.006%). This missense change has been observed in individuals with Noonan syndrome (PMID: 11704759, 11992261, 12325025, 12960218, 16498234, 21407260). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13333). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PTPN11 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 22711529). For these reasons, this variant has been classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(May 18, 2017)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
LEOPARD syndrome 1
Metachondromatosis Noonan syndrome 1 Juvenile myelomonocytic leukemia |
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611303.1
First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(May 02, 2016)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Noonan syndrome 3 |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698066.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
show
Variant summary: The c.188A>G variant affects a conserved nucleotide, resulting in amino acid change from Tyr to Cys. 4/4 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is found in 1/121890 control chromosomes at a frequency of 0.0000082, which does not exceed maximal expected frequency of a pathogenic allele (0.0000625). The variant has been reported in numerous affected individuals and families in the literature and has been shown to segregate with disease in affected families. The variant is considered a common pathogenic variant. In addition, multiple reputable clinical laboratory and database classified this variant as Pathogenic. Taken together, this variant was classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Apr 20, 2017)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Noonan syndrome
(Autosomal dominant inheritance)
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061294.6
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Comment:
show
The p.Tyr63Cys variant in PTPN11 has been reported in >40 individuals with Noona n syndrome, occurred de novo in some sporadic cases and segregated with disease in numerous families (Tartaglia 2002, Kosaki 2002, Maheshwari 2002, Musante 2003 , Loh 2004, Kratz 2005, Takahashi 2006, Becker 2007, Jongmans 2011, Simsek-Kiper 2012, LMM data). In addition, this variant has been identified as a somatic var iant in one individual with chronic myelomonocytic leukemia (CMML; Loh 2004) and as a germline variant in two individuals with both clinical features of Noonan syndrome and a malignancy (precursor B-ALL and basal cell carcinoma; Jongmans 20 11). This variant has also been identified in 1/17248 East Asian chromosomes and 1/33576 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Moreov er, the p.Tyr63Cys variant has been classified as pathogenic on April 3, 2018 by the ClinGen-approved RASopathy Expert Panel (ClinVar SCV000616372.1). In summar y, this variant meets criteria to be classified as pathogenic for Noonan syndrom e in an autosomal dominant manner based upon presence in multiple affected indiv iduals, de novo occurrences and segregation studies. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM6_Strong. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: not provided
Number of individuals with the variant: 52
|
|
|
Pathogenic
(Dec 10, 2018)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Noonan syndrome 1
LEOPARD syndrome 1 Metachondromatosis |
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV001423672.1
First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020 |
Comment:
show
[ACMG/AMP/ClinGen RASopathy: PS1, PS3, PS4, PP1_Strong, PM1, PP2, PP3] This alteration has an amino acid change previously established as pathogenic (regardless of nucleotide change) [PS1], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], has a prevalence that is significantly increased compared with controls (RR/OR > 5; CI does not include 1.0) [PS4], has been shown to cosegregate with disease in multiple affected family members [PP1_Strong], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3]. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Jul 10, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755589.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
Observation 1
Collection method: clinical testing
Allele origin: de novo
Affected status: yes
Indication for testing: Multiple Congenital Anomalies
Platform type: next-gen sequencing
|
|
|
Pathogenic
(Oct 01, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Noonan syndrome 1 |
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976777.1
First in ClinVar: Mar 25, 2020 Last updated: Mar 25, 2020 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
|
|
|
Pathogenic
(Apr 26, 2017)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
B lymphoblastic leukemia lymphoma, no ICD-O subtype
Lymphoma |
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV000853187.2
First in ClinVar: Nov 25, 2018 Last updated: Apr 13, 2025 |
Comment:
show
This is a missense alteration in which an A is replaced by a G at coding nucleotide 188 and is predicted to change a Tyrosine to a Cysteine at amino acid codon 63. Classification criteria: PS1, PS3, PM1, PM2, PP3. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Sex: female
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Noonan syndrome 1
LEOPARD syndrome 1 Metachondromatosis Juvenile myelomonocytic leukemia
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. |
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV002495907.3
First in ClinVar: Apr 11, 2022 Last updated: May 03, 2025 |
Comment:
show
This variant has been reported in the literature in at least 10 individuals with a clinical diagnosis or suspicion of Noonan syndrome, segregating with disease in more than 15 affected family members (Selected publications: Maheshwari 2002 PMID:12325025; Musante 2003 PMID:12634870; Jongmans 2011 PMID:21407260; Athota 2020 PMID:32164556). This variant is present in 0.005% (1/18394) of East Asian alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/12-112888172-A-G?dataset=gnomad_r2_1). Please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with many laboratories and the ClinGen RASopathy Variant Curation Expert Panel classifying it as pathogenic (Variation ID:13333). This variant is located at a residue directly involved in interactions between N-SH2 and PTPN domains (Gelb 2018 PMID:29493581). An in vitro functional study showed that this variant impacts protein structure, resulting in increased protein activity (Martinelli 2012 PMID:22711529). However, this study study may not accurately represent in vivo biological function. PTPN11 has a low rate of benign missense variation and pathogenic missense variation is common (Gelb 2018 PMID:29493581). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In summary, this variant is classified as pathogenic (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
pathogenic
(Jan 04, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Noonan syndrome 1 |
Laboratoire de Génétique Moléculaire, CHU Bordeaux
Accession: SCV006278246.1
First in ClinVar: Jul 19, 2025 Last updated: Jul 19, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Noonan syndrome 1 |
Juno Genomics, Hangzhou Juno Genomics, Inc
Accession: SCV005416165.2
First in ClinVar: Nov 30, 2024 Last updated: Oct 05, 2025 |
Comment:
show
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Jun 27, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Noonan syndrome 1 |
3billion
Accession: SCV002012314.4
First in ClinVar: Nov 13, 2021 Last updated: Oct 25, 2025 |
Comment:
show
The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 22711529). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.95 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.96 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013333 /PMID: 11704759).The variant has been previously reported as de novo in a similarly affected individual (3billion dataset).The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 11704759, 12325025, 12634870, 16498234). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Method: exome sequencing
|
|
|
Pathogenic
(Jun 19, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Noonan syndrome |
Division of Genetic & Genomic Pathology, Hong Kong Children's Hospital
Accession: SCV007539705.1
First in ClinVar: Apr 12, 2026 Last updated: Apr 12, 2026 |
Comment:
show
PTPN11 c.188A>G p.(Tyr63Cys) variant has been classified as pathogenic by the ClinGen RASopathy Variant Curation Expert Panel (ClinVar accession: VCV000013333.85, PMID: 29493581). (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Dec 05, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Noonan syndrome 1
(Autosomal dominant inheritance)
|
Variantyx, Inc.
Accession: SCV007593898.1
First in ClinVar: May 16, 2026 Last updated: May 16, 2026 |
Comment:
show
This is a nonsynonymous variant in the PTPN11 gene (OMIM: 176876). Pathogenic variants in this gene have been associated with autosomal dominant Noonan syndrome 1. This variant has been reported in at least 15 unrelated affected individuals (PMID: 16498234, 12634870, 12325025, 11704759) (PS4_Moderate) and it has been observed to segregate with disease in at least 10 individuals from multiple families (PMID: 11704759, 11992261, 21407260) (PP1). Functional studies have shown that this variant alters PTPN11 protein function (PMID: 22711529) (PS3) and multiple computational algorithms predict a deleterious effect for this variant (REVEL score: 0.955) (PP3). Moreover, this variant lies within a known hotspot for pathogenic variants or a well-established critical functional domain of the PTPN11 protein (PMID: 29493581) (PM1). It has a 0.0022% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on the evidence, this variant is classified as pathogenic for autosomal dominant Noonan syndrome 1. Inheritance from an unaffected or mildly affected parent has been reported, consistent with incomplete penetrance and variable expressivity (PMID: 22465605, 22465605). (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Nov 19, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Dasa
Accession: SCV007599371.1
First in ClinVar: May 30, 2026 Last updated: May 30, 2026 |
Comment:
show
NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys) is a missense variant that results in the substitution of tyrosine with cysteine. The affected residue or protein region has prior evidence supporting clinical relevance. Segregation evidence has been reported in affected families. Functional evidence supports a deleterious effect on the gene or gene product (PMID: 22711529; PMID: 12634870; PMID: 12325025; PMID: 32164556; PMID: 16498234). This variant has been recurrently observed in individuals with related phenotype (PMID: 22711529; PMID: 12634870; PMID: 12325025; PMID: 32164556; PMID: 16498234). Multiple computational predictions support a deleterious effect on the gene or gene product. Based on the available data, this variant is classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Oct 01, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246728.39
First in ClinVar: May 12, 2020 Last updated: Jul 27, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 5
|
|
|
Pathogenic
(Jan 07, 2015)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Noonan syndrome |
Blueprint Genetics
Accession: SCV000207167.3
First in ClinVar: Feb 06, 2015 Last updated: Apr 09, 2018 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Jun 15, 2017)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Athena Diagnostics
Accession: SCV000614839.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Nov 01, 2016)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Noonan syndrome 1 |
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000782248.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Noonan syndrome 1 |
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital
Accession: SCV000992395.1
First in ClinVar: Feb 17, 2020 Last updated: Feb 17, 2020 |
Observation 1
Collection method: case-control
Allele origin: de novo
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
hearing loss (present) , Café au lait macules (present) , Postnatal growth retardation (present) , Ocular hypertelorism (present)
Family history: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Noonan syndrome 1 |
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn
Accession: SCV000999303.1
First in ClinVar: Dec 01, 2019 Last updated: Dec 01, 2019 |
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Hypertelorism (present) , Epicanthus (present) , Cryptorchidism (present) , Bruising susceptibility (present) , Abnormality of the thorax (present) , Pulmonic stenosis (present) , Ptosis (present)
|
|
|
Pathogenic
(May 23, 2019)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Noonan syndrome 1 |
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001190264.1
First in ClinVar: Feb 17, 2020 Last updated: Feb 17, 2020 |
Observation: 1
Collection method: clinical testing
Allele origin: de novo
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: de novo
Affected status: yes
|
|
|
Pathogenic
(Jul 12, 2018)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Noonan syndrome 1 |
CENTOGENE GmbH and LLC - Guiding Precision Medicine
Accession: SCV002059442.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Sep 14, 2020)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Noonan syndrome and Noonan-related syndrome |
Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002060861.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Jan 20, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501823.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Secondary finding: no
Platform type: NGS
|
|
|
Pathogenic
(Aug 11, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
GeneDx
Accession: SCV000057373.14
First in ClinVar: Jul 03, 2013 Last updated: Mar 04, 2023 |
Comment:
show
Published functional studies demonstrate that Y63C perturbs the autoinhibitory interaction between the N-SH2 and protein-tyrosine phosphatase domains, which is required to maintain SHP2 in its catalytically inactive state (Martinelli et al., 2012); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21407260, 12325025, 24803665, 11704759, 30055033, 30417923, 32164556, 24219368, 22711529, 12634870, 26242988, 25156961, 30692697, 30050098, 29907801, 31219622, 31560489, 32371413, 32901917, 11992261, 9491886, 16053901, 29493581) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Apr 06, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
LEOPARD syndrome 1 |
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807148.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
show
ACMG classification criteria: PS3 strong, PS4 strong, PM1 moderated, PP1 strong, PP2 supporting, PP3 supporting (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Telecanthus (present) , Joint hypermobility (present) , Abnormal nasal morphology (present) , Cryptorchidism (present) , Round ear (present) , Clinodactyly of the 5th finger (present)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
|
|
|
Pathogenic
(Feb 14, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
LEOPARD syndrome 1 |
Baylor Genetics
Accession: SCV003836226.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Feb 12, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Noonan syndrome 1 |
Baylor Genetics
Accession: SCV000854621.2
First in ClinVar: May 29, 2016 Last updated: Mar 11, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Feb 14, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Metachondromatosis |
Baylor Genetics
Accession: SCV003835598.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Jul 01, 2023)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
RASopathy |
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand
Accession: SCV004034113.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
Observation: 1
Collection method: research
Allele origin: germline
Affected status: yes
Observation 1
Collection method: research
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
PTPN11-Related Disorders
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046310.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
show
This variant has been previously reported as a heterozygous change in patients with PTPN11-related disorders (PMID: 16498234, 12634870, 12325025, 11704759, 21407260). Functional studies suggest that this variant impacts protein structure, resulting in increased protein activity (PMID: 22711529). The c.188A>G (p.Tyr63Cys) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/251010) and thus is presumed to be rare. Based on the available evidence, the c.188A>G (p.Tyr63Cys) variant is classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Aug 16, 2023)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000884430.3
First in ClinVar: Dec 06, 2016 Last updated: Feb 20, 2024 |
Comment:
show
The PTPN11 c.188A>G; p.Tyr63Cys variant (rs121918459) has been reported in multiple patients diagnosed with Noonan syndrome (Tartaglia 2001, Jongmans 2011, Martinelli 2012, Hashida 2013, Lepri 2014, Okamoto 2015). This variant is found on only three chromosomes (3/251010 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism, and it is listed as pathogenic in ClinVar by multiple clinical laboratories (Variation ID: 13333). The p.Tyr63Cys variant is located in a structurally important region of the catalytic N-terminal SH2 domain of PTPN11 (Hof 1998), and several additional variants in neighboring codons (p.Asp61Asn, p.Asp61Gly, p.Tyr62Asp, p.Tyr62Asn) have also been identified in individuals with Noonan syndrome (Jongmans 2011, Tartaglia 2002, Tartaglia 2006). Functional characterization of the p.Tyr63Cys variant protein indicates over-activation of p38alpha MAP kinase and phosphorERK1/2 upon growth factor signaling (Martinelli 2012, Hashida 2013), consistent with the established disease mechanisms of Noonan syndrome. Based on available information, the p.Tyr63Cys variant is classified as pathogenic. References: Hashida N et al. MAPK activation in mature cataract associated with Noonan syndrome. BMC Ophthalmol. 2013 Nov 12;13:70. PMID: 24219368 Hof P et al. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998 Feb 20;92(4):441-50. PMID: 9491886 Jongmans M et al. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet. 2011 Aug;19(8):870-4. PMID: 21407260 Lepri et al. Diagnosis of Noonan syndrome and related disorders using target next generation sequencing. BMC Med Genet. 2014 Jan 23;15:14. PMID: 24451042 Martinelli S et al. Counteracting effects operating on Src homology 2 domain-containing protein-tyrosine phosphatase 2 (SHP2) function drive selection of the recurrent Y62D and Y63C substitutions in Noonan syndrome. J Biol Chem. 2012 Aug 3;287(32):27066-77. PMID: 22711529 Okamoto N et al. Targeted next-generation sequencing in the diagnosis of neurodevelopmental disorders. Clin Genet. 2015 Sep;88(3):288-92. PMID: 25156961 Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001 Dec;29(4):465-8. PMID: 11704759 Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 Jun;70(6):1555-63. PMID: 11992261 Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 Feb;78(2):279-90. PMID: 16358218 (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Aug 21, 2023)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005197295.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Aug 29, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Noonan syndrome 1 |
Institute of Immunology and Genetics Kaiserslautern
Accession: SCV005382133.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 |
Comment:
show
ACMG Criteria: PS1, PS3, PS4, PM1, PM2_P, PP1, PP3, PP5; Variant was found in heterozygous state (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Clinical Features:
Floppy infant (present) , Respiratory insufficiency due to muscle weakness (present) , Infantile onset (present) , Abnormal heart morphology (present) , Ventricular septal defect (present) , Renal insufficiency (present) , Hypocalcemia (present)
|
|
|
Pathogenic
(Sep 16, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Molecular Diagnostics Laboratory, Catalan Institute of Oncology
Accession: SCV005902112.1
First in ClinVar: Apr 07, 2025 Last updated: Apr 07, 2025 |
Comment:
show
PS4, PP1_strong, PM1, PS3_supporting, PP2, PP3 c.188A>G, located in exon 3 of the PTPN11 gene, is predicted to result in the substitution of tyrosine by cysteine at codon 63, p.(Tyr63Cys). This variant is found in 3/236472 alleles at a frequency of 0.001% in the gnomAD v2.1.1 database, non-cancer dataset. It has been observed in multiple affected individuals (PMID: 16498234, 12634870, 12325025, 11704759) (PS4, PP1_strong). This position affects a (potentially) clinically important functional domain (PM1). PTPN11 gene has a low rate of benign missense variants (PP2). The SpliceAI algorithm predicts no significant impact on splicing. The REVEL meta-predictor score for this variant (0.984) suggests a deleterious effect on protein function according to Pejaver 2022 thresholds (PMID: 36413997) (PP3). In vitro functional assays suggest that the p.Tyr63Cys variant could affect the protein's function (PMID:22711529) (PS3_supporting). This variant has been reported in the ClinVar database (46x pathogenic, 1x likely pathogenic), and in the LOVD database (21x likely pathogenic, 5x pathogenic), furthermore, it has been classified by the ClinGen RASopathy Variant Curation Expert Panel as pathogenic. Based on currently available information, the variant c.188A>G should be considered a pathogenic variant. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Mar 01, 2013)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Eurofins Ntd Llc (ga)
Accession: SCV000058290.10
First in ClinVar: Apr 04, 2013 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 4
Zygosity: 4 Single Heterozygotes
Sex: mixed
|
|
|
Pathogenic
(Sep 21, 2015)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Molecular Diagnostics Lab, Nemours Children's Health, Delaware
Accession: SCV000265840.2
First in ClinVar: Jun 29, 2015 Last updated: Apr 13, 2025 |
Observation:
2
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Facial features resembling Noonan Syndrome (present) , Bitemporal narrowing (present) , Pulmonic stenosis (present) , Cryptorchidism (present)
Age: 0-9 years
Sex: male
Observation 2
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Congenital stenosis of pulmonary valve (present) , Congenital pulmonary insufficiency (present) , Paroxysmal superventricular tachcardia (present)
Age: 0-9 years
Sex: female
|
|
|
Pathogenic
(Mar 28, 2017)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Noonan syndrome 1
(Autosomal dominant inheritance)
|
Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV000746635.2 First in ClinVar: May 29, 2016 Last updated: Apr 13, 2025 |
Observation 1
Collection method: clinical testing
Allele origin: de novo
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
Vascular skin abnormality (present) , Patent ductus arteriosus (present) , Osteopenia (present) , Narrow forehead (present) , Myalgia (present) , Muscle weakness (present) , Menorrhagia (present) , Lumbar scoliosis (present) , Long toe (present) , Long face (present) , Joint laxity (present) , High, narrow palate (present) , Fatigue (present) , Dyspnea (present) , Delayed puberty (present) , Cupped ear (present) , Capillary hemangiomas (present) , Bruising susceptibility (present) , Bilateral ptosis (present) , Atrioventricular canal defect (present) , Absent patellar reflexes (present) , Abnormality of skeletal maturation (present) , Abnormality of bone mineral density (present)
Zygosity: 1 Single Heterozygote
Age: 30-39 years
Sex: female
Ethnicity/Population group: White
Platform type: exome sequencing
Platform name: HiSeq
Testing laboratory: Baylor Genetics
Date variant was reported to submitter: 2017-03-28
Testing laboratory interpretation: Pathogenic
|
|
|
Pathogenic
(Sep 15, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided
(Autosomal dominant inheritance)
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001905629.2
First in ClinVar: Sep 26, 2021 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Clinical Features:
Epicanthus (present) , Hypertelorism (present) , Low-set ears (present) , Failure to thrive (present) , Abnormal cardiac septum morphology (present) , Short stature (present) , Decreased body weight (present) , Wide intermamillary distance (present) , Atrioventricular canal defect (present)
Sex: female
|
|
|
Pathogenic
(Aug 16, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Noonan syndrome 1 |
MGZ Medical Genetics Center
Accession: SCV002581037.2
First in ClinVar: Oct 15, 2022 Last updated: Apr 13, 2025
Comment:
ACMG criteria applied: PS3, PS4, PP1_STR, PM1, PP2, PP3
|
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Sex: female
|
|
|
Pathogenic
(Sep 24, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Noonan syndrome 1 |
Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam
Accession: SCV006551176.1
First in ClinVar: Mar 28, 2026 Last updated: Mar 28, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Geographic origin: Vietnam
|
|
|
Pathogenic
(Feb 12, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Monogenic short stature
|
Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service
Accession: SCV007517187.1
First in ClinVar: Mar 07, 2026 Last updated: Mar 07, 2026 |
Comment:
show
The gene PTPN11 has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 3.13. The gene PTPN11 contains 144 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. (PP2 - Supporting) | 28 variants within 6 amino acid positions of the variant p.Tyr63Cys have been shown to be pathogenic, while none have been shown to be benign. (PM1 - Moderate) | The p.Tyr63Cys missense variant is predicted to be damaging by both SIFT and PolyPhen2. The tyrosine residue at codon 63 of PTPN11 is conserved in all mammalian species. The nucleotide c.188 in PTPN11 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. (PP3 - Supporting) | Functional studies demonstrate that this variant has a damaging effect on the gene or gene product (PS3 - Strong) | The variant cosegregates with the disease in multiple affected family members. (PP1_Strong - Strong) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Jun 01, 2007)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
NOONAN SYNDROME 1 |
OMIM
Accession: SCV000034509.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 09, 2019 |
Observation: 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Comment on evidence:
In 2 unrelated families, Maheshwari et al. (2002) found that probands with Noonan syndrome (NS1; 163950) had a tyr63-to-cys (Y63C) mutation in exon 3. This … (more)
In 2 unrelated families, Maheshwari et al. (2002) found that probands with Noonan syndrome (NS1; 163950) had a tyr63-to-cys (Y63C) mutation in exon 3. This same mutation was identified by Tartaglia et al. (2001). This mutation was also identified by Kosaki et al. (2002) in 2 patients. See 176876.0004 and Becker et al. (2007). (less)
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Study: VKGL Data-share Consensus
Accession: SCV001956732.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
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Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Rasopathy |
Baylor Genetics
Accession: SCV000196657.1
First in ClinVar: Jan 16, 2015 Last updated: Jan 16, 2015 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
|
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Pathogenic
(Jan 15, 2015)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV000207652.1
First in ClinVar: Feb 19, 2015 Last updated: Feb 19, 2015 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
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Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV001931284.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
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Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Noonan syndrome 1 |
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand
Accession: SCV003840159.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Observation 1
Collection method: research
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Nov 02, 2023)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Noonan syndrome 1 |
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Accession: SCV004101114.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
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Pathogenic
(Jul 04, 2024)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
PTPN11-related condition
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004103329.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
show
The PTPN11 c.188A>G variant is predicted to result in the amino acid substitution p.Tyr63Cys. This variant has been reported in many unrelated individuals with Noonan syndrome and was found to occur de novo in several cases and segregated with disease in many families (Tartaglia et al. 2001. PubMed ID: 11704759; Maheshwari et al. 2002. PubMed ID: 12325025; Jongmans et al. 2011. PubMed ID: 21407260; Okamoto et al. 2015. PubMed ID: 25156961). Functional studies indicate that the p.Tyr63Cys variant alters the functional regulation of SHP2 protein by affecting the stability between N-SH2 and PTP domains (Martinelli et al. 2012. PubMed ID: 22711529). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
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|
Pathogenic
(Apr 11, 2024)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Noonan syndrome 1 |
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein
Accession: SCV006323732.1
First in ClinVar: Sep 06, 2025 Last updated: Sep 06, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
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Uncertain significance
(Feb 14, 2023)
N
Not contributing to aggregate classification
|
Flagged submission
flagged submission
Reason: Conflicts with expert reviewed submission without evidence to support different classification
Source: ClinGen
|
Noonan syndrome 1
(Autosomal dominant inheritance)
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004176586.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
show
The missense c.188A>G(p.Tyr63Cys) variant in PTPN11 gene has been reported previously in heterozygous state in individual(s) affected with Noonan syndrome (Takahashi et al., 2006). Experimental studies have shown that this missense change affects PTPN11 function (Martinelli S et al., 2012). This variant is reported with the allele frequency of 0.001% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. The amino acid Tyr at position 63 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Tyr63Cys in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Clinical Features:
Abnormality of the nervous system (present)
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| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
PS3, PS4, PM6, PP1, PP3, PP5
Comment:
PP1_strong, PP2, PP3, PM1, PS3_moderate
Comment:
This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes); The variant has strong previous evidence of pathogenicity in unrelated individuals with Noonan syndrome. It is a 3-star pathogenic variant in ClinVar (reviewed by the ClinGen RASopathy Variant Curation Expert Panel), and is reported in the literature in individuals with Noonan syndrome (PMIDs: 11704759; 12325025; 12634870); The variant has strong evidence for segregation with disease in multiple families (PMID: 12325025; 12634870); Variant is located in a hotspot region or cluster of pathogenic variants (N-SH2 domain; DECIPHER); Missense variant consistently predicted to be damaging by multiple in silico tools and is highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from tyrosine to cysteine; This variant is heterozygous; This gene is known to be associated with autosomal dominant disease; Both loss of function and gain of function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250), and Noonan syndrome with multiple lentigines have been associated with loss of function variants, whereas Noonan syndrome 1 (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 24935154, 21533187); Variants in this gene are known to have variable expressivity (PMID: 20301303); This variant has been shown to be maternally inherited by trio analysis.
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 63 of the PTPN11 protein (p.Tyr63Cys). This variant is present in population databases (rs121918459, gnomAD 0.006%). This missense change has been observed in individuals with Noonan syndrome (PMID: 11704759, 11992261, 12325025, 12960218, 16498234, 21407260). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13333). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PTPN11 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 22711529). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: The c.188A>G variant affects a conserved nucleotide, resulting in amino acid change from Tyr to Cys. 4/4 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is found in 1/121890 control chromosomes at a frequency of 0.0000082, which does not exceed maximal expected frequency of a pathogenic allele (0.0000625). The variant has been reported in numerous affected individuals and families in the literature and has been shown to segregate with disease in affected families. The variant is considered a common pathogenic variant. In addition, multiple reputable clinical laboratory and database classified this variant as Pathogenic. Taken together, this variant was classified as Pathogenic.
Comment:
The p.Tyr63Cys variant in PTPN11 has been reported in >40 individuals with Noona n syndrome, occurred de novo in some sporadic cases and segregated with disease in numerous families (Tartaglia 2002, Kosaki 2002, Maheshwari 2002, Musante 2003 , Loh 2004, Kratz 2005, Takahashi 2006, Becker 2007, Jongmans 2011, Simsek-Kiper 2012, LMM data). In addition, this variant has been identified as a somatic var iant in one individual with chronic myelomonocytic leukemia (CMML; Loh 2004) and as a germline variant in two individuals with both clinical features of Noonan syndrome and a malignancy (precursor B-ALL and basal cell carcinoma; Jongmans 20 11). This variant has also been identified in 1/17248 East Asian chromosomes and 1/33576 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Moreov er, the p.Tyr63Cys variant has been classified as pathogenic on April 3, 2018 by the ClinGen-approved RASopathy Expert Panel (ClinVar SCV000616372.1). In summar y, this variant meets criteria to be classified as pathogenic for Noonan syndrom e in an autosomal dominant manner based upon presence in multiple affected indiv iduals, de novo occurrences and segregation studies. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM6_Strong.
Comment:
[ACMG/AMP/ClinGen RASopathy: PS1, PS3, PS4, PP1_Strong, PM1, PP2, PP3] This alteration has an amino acid change previously established as pathogenic (regardless of nucleotide change) [PS1], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], has a prevalence that is significantly increased compared with controls (RR/OR > 5; CI does not include 1.0) [PS4], has been shown to cosegregate with disease in multiple affected family members [PP1_Strong], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3].
Comment:
PS3, PM1, PM2, PP2, PP3, PP5
Comment:
This is a missense alteration in which an A is replaced by a G at coding nucleotide 188 and is predicted to change a Tyrosine to a Cysteine at amino acid codon 63. Classification criteria: PS1, PS3, PM1, PM2, PP3.
Comment:
This variant has been reported in the literature in at least 10 individuals with a clinical diagnosis or suspicion of Noonan syndrome, segregating with disease in more than 15 affected family members (Selected publications: Maheshwari 2002 PMID:12325025; Musante 2003 PMID:12634870; Jongmans 2011 PMID:21407260; Athota 2020 PMID:32164556). This variant is present in 0.005% (1/18394) of East Asian alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/12-112888172-A-G?dataset=gnomad_r2_1). Please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with many laboratories and the ClinGen RASopathy Variant Curation Expert Panel classifying it as pathogenic (Variation ID:13333). This variant is located at a residue directly involved in interactions between N-SH2 and PTPN domains (Gelb 2018 PMID:29493581). An in vitro functional study showed that this variant impacts protein structure, resulting in increased protein activity (Martinelli 2012 PMID:22711529). However, this study study may not accurately represent in vivo biological function. PTPN11 has a low rate of benign missense variation and pathogenic missense variation is common (Gelb 2018 PMID:29493581). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In summary, this variant is classified as pathogenic
Comment:
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 22711529). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.95 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.96 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013333 /PMID: 11704759).The variant has been previously reported as de novo in a similarly affected individual (3billion dataset).The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 11704759, 12325025, 12634870, 16498234). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in pilocytic astrocytoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 15834506, 14644997). 3) Diagnostic significance based on multiple small studies (Evidence Level C; PMIDs: 28912153, 23817572, 19621452, 28328117).
Comment:
PTPN11 c.188A>G p.(Tyr63Cys) variant has been classified as pathogenic by the ClinGen RASopathy Variant Curation Expert Panel (ClinVar accession: VCV000013333.85, PMID: 29493581).
Comment:
This is a nonsynonymous variant in the PTPN11 gene (OMIM: 176876). Pathogenic variants in this gene have been associated with autosomal dominant Noonan syndrome 1. This variant has been reported in at least 15 unrelated affected individuals (PMID: 16498234, 12634870, 12325025, 11704759) (PS4_Moderate) and it has been observed to segregate with disease in at least 10 individuals from multiple families (PMID: 11704759, 11992261, 21407260) (PP1). Functional studies have shown that this variant alters PTPN11 protein function (PMID: 22711529) (PS3) and multiple computational algorithms predict a deleterious effect for this variant (REVEL score: 0.955) (PP3). Moreover, this variant lies within a known hotspot for pathogenic variants or a well-established critical functional domain of the PTPN11 protein (PMID: 29493581) (PM1). It has a 0.0022% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on the evidence, this variant is classified as pathogenic for autosomal dominant Noonan syndrome 1. Inheritance from an unaffected or mildly affected parent has been reported, consistent with incomplete penetrance and variable expressivity (PMID: 22465605, 22465605).
Comment:
NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys) is a missense variant that results in the substitution of tyrosine with cysteine. The affected residue or protein region has prior evidence supporting clinical relevance. Segregation evidence has been reported in affected families. Functional evidence supports a deleterious effect on the gene or gene product (PMID: 22711529; PMID: 12634870; PMID: 12325025; PMID: 32164556; PMID: 16498234). This variant has been recurrently observed in individuals with related phenotype (PMID: 22711529; PMID: 12634870; PMID: 12325025; PMID: 32164556; PMID: 16498234). Multiple computational predictions support a deleterious effect on the gene or gene product. Based on the available data, this variant is classified as pathogenic.
Comment:
PTPN11: PP1:Strong, PS2, PS4, PM1, PM2, PP2, PP3, PS3:Supporting
Comment:
Published functional studies demonstrate that Y63C perturbs the autoinhibitory interaction between the N-SH2 and protein-tyrosine phosphatase domains, which is required to maintain SHP2 in its catalytically inactive state (Martinelli et al., 2012); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21407260, 12325025, 24803665, 11704759, 30055033, 30417923, 32164556, 24219368, 22711529, 12634870, 26242988, 25156961, 30692697, 30050098, 29907801, 31219622, 31560489, 32371413, 32901917, 11992261, 9491886, 16053901, 29493581)
Comment:
ACMG classification criteria: PS3 strong, PS4 strong, PM1 moderated, PP1 strong, PP2 supporting, PP3 supporting
Comment:
This variant has been previously reported as a heterozygous change in patients with PTPN11-related disorders (PMID: 16498234, 12634870, 12325025, 11704759, 21407260). Functional studies suggest that this variant impacts protein structure, resulting in increased protein activity (PMID: 22711529). The c.188A>G (p.Tyr63Cys) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/251010) and thus is presumed to be rare. Based on the available evidence, the c.188A>G (p.Tyr63Cys) variant is classified as Pathogenic.
Comment:
The PTPN11 c.188A>G; p.Tyr63Cys variant (rs121918459) has been reported in multiple patients diagnosed with Noonan syndrome (Tartaglia 2001, Jongmans 2011, Martinelli 2012, Hashida 2013, Lepri 2014, Okamoto 2015). This variant is found on only three chromosomes (3/251010 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism, and it is listed as pathogenic in ClinVar by multiple clinical laboratories (Variation ID: 13333). The p.Tyr63Cys variant is located in a structurally important region of the catalytic N-terminal SH2 domain of PTPN11 (Hof 1998), and several additional variants in neighboring codons (p.Asp61Asn, p.Asp61Gly, p.Tyr62Asp, p.Tyr62Asn) have also been identified in individuals with Noonan syndrome (Jongmans 2011, Tartaglia 2002, Tartaglia 2006). Functional characterization of the p.Tyr63Cys variant protein indicates over-activation of p38alpha MAP kinase and phosphorERK1/2 upon growth factor signaling (Martinelli 2012, Hashida 2013), consistent with the established disease mechanisms of Noonan syndrome. Based on available information, the p.Tyr63Cys variant is classified as pathogenic. References: Hashida N et al. MAPK activation in mature cataract associated with Noonan syndrome. BMC Ophthalmol. 2013 Nov 12;13:70. PMID: 24219368 Hof P et al. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998 Feb 20;92(4):441-50. PMID: 9491886 Jongmans M et al. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet. 2011 Aug;19(8):870-4. PMID: 21407260 Lepri et al. Diagnosis of Noonan syndrome and related disorders using target next generation sequencing. BMC Med Genet. 2014 Jan 23;15:14. PMID: 24451042 Martinelli S et al. Counteracting effects operating on Src homology 2 domain-containing protein-tyrosine phosphatase 2 (SHP2) function drive selection of the recurrent Y62D and Y63C substitutions in Noonan syndrome. J Biol Chem. 2012 Aug 3;287(32):27066-77. PMID: 22711529 Okamoto N et al. Targeted next-generation sequencing in the diagnosis of neurodevelopmental disorders. Clin Genet. 2015 Sep;88(3):288-92. PMID: 25156961 Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001 Dec;29(4):465-8. PMID: 11704759 Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 Jun;70(6):1555-63. PMID: 11992261 Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 Feb;78(2):279-90. PMID: 16358218
Comment:
ACMG Criteria: PS1, PS3, PS4, PM1, PM2_P, PP1, PP3, PP5; Variant was found in heterozygous state
Comment:
PS4, PP1_strong, PM1, PS3_supporting, PP2, PP3 c.188A>G, located in exon 3 of the PTPN11 gene, is predicted to result in the substitution of tyrosine by cysteine at codon 63, p.(Tyr63Cys). This variant is found in 3/236472 alleles at a frequency of 0.001% in the gnomAD v2.1.1 database, non-cancer dataset. It has been observed in multiple affected individuals (PMID: 16498234, 12634870, 12325025, 11704759) (PS4, PP1_strong). This position affects a (potentially) clinically important functional domain (PM1). PTPN11 gene has a low rate of benign missense variants (PP2). The SpliceAI algorithm predicts no significant impact on splicing. The REVEL meta-predictor score for this variant (0.984) suggests a deleterious effect on protein function according to Pejaver 2022 thresholds (PMID: 36413997) (PP3). In vitro functional assays suggest that the p.Tyr63Cys variant could affect the protein's function (PMID:22711529) (PS3_supporting). This variant has been reported in the ClinVar database (46x pathogenic, 1x likely pathogenic), and in the LOVD database (21x likely pathogenic, 5x pathogenic), furthermore, it has been classified by the ClinGen RASopathy Variant Curation Expert Panel as pathogenic. Based on currently available information, the variant c.188A>G should be considered a pathogenic variant.
Comment:
The gene PTPN11 has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 3.13. The gene PTPN11 contains 144 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. (PP2 - Supporting) | 28 variants within 6 amino acid positions of the variant p.Tyr63Cys have been shown to be pathogenic, while none have been shown to be benign. (PM1 - Moderate) | The p.Tyr63Cys missense variant is predicted to be damaging by both SIFT and PolyPhen2. The tyrosine residue at codon 63 of PTPN11 is conserved in all mammalian species. The nucleotide c.188 in PTPN11 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. (PP3 - Supporting) | Functional studies demonstrate that this variant has a damaging effect on the gene or gene product (PS3 - Strong) | The variant cosegregates with the disease in multiple affected family members. (PP1_Strong - Strong)
Comment:
Variant classified using ACMG guidelines
Comment:
The PTPN11 c.188A>G variant is predicted to result in the amino acid substitution p.Tyr63Cys. This variant has been reported in many unrelated individuals with Noonan syndrome and was found to occur de novo in several cases and segregated with disease in many families (Tartaglia et al. 2001. PubMed ID: 11704759; Maheshwari et al. 2002. PubMed ID: 12325025; Jongmans et al. 2011. PubMed ID: 21407260; Okamoto et al. 2015. PubMed ID: 25156961). Functional studies indicate that the p.Tyr63Cys variant alters the functional regulation of SHP2 protein by affecting the stability between N-SH2 and PTP domains (Martinelli et al. 2012. PubMed ID: 22711529). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic.
Comment:
The missense c.188A>G(p.Tyr63Cys) variant in PTPN11 gene has been reported previously in heterozygous state in individual(s) affected with Noonan syndrome (Takahashi et al., 2006). Experimental studies have shown that this missense change affects PTPN11 function (Martinelli S et al., 2012). This variant is reported with the allele frequency of 0.001% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. The amino acid Tyr at position 63 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Tyr63Cys in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Noonan Syndrome. | Adam MP | - | 2025 | PMID: 20301303 |
| Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders. | Marinakis NM | American journal of medical genetics. Part A | 2021 | PMID: 34008892 |
| Diagnostic yield and clinical utility of whole exome sequencing using an automated variant prioritization system, EVIDENCE. | Seo GH | Clinical genetics | 2020 | PMID: 32901917 |
| Disease-associated mosaic variation in clinical exome sequencing: a two-year pediatric tertiary care experience. | Miller CR | Cold Spring Harbor molecular case studies | 2020 | PMID: 32371413 |
| Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations. | Athota JP | BMC medical genetics | 2020 | PMID: 32164556 |
| Clinical and molecular characterization of children with Noonan syndrome and other RASopathies in Argentina. | Chinton J | Archivos argentinos de pediatria | 2019 | PMID: 31560489 |
| Molecular and phenotypic spectrum of Noonan syndrome in Chinese patients. | Li X | Clinical genetics | 2019 | PMID: 31219622 |
| Non-invasive prenatal sequencing for multiple Mendelian monogenic disorders using circulating cell-free fetal DNA. | Zhang J | Nature medicine | 2019 | PMID: 30692697 |
| Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation. | Bessis D | The British journal of dermatology | 2019 | PMID: 30417923 |
| Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions. | Leach NT | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29907801 |
| Nonreentrant atrial tachycardia occurs independently of hypertrophic cardiomyopathy in RASopathy patients. | Levin MD | American journal of medical genetics. Part A | 2018 | PMID: 30055033 |
| ClinGen's RASopathy Expert Panel consensus methods for variant interpretation. | Gelb BD | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29493581 |
| Long-term efficacy of recombinant human growth hormone therapy in short-statured patients with Noonan syndrome. | Jeong I | Annals of pediatric endocrinology & metabolism | 2016 | PMID: 27104176 |
| Nutritional aspects of Noonan syndrome and Noonan-related disorders. | da Silva FM | American journal of medical genetics. Part A | 2016 | PMID: 27038324 |
| Mutation Spectrum and Phenotypic Features in Noonan Syndrome with PTPN11 Mutations: Definition of Two Novel Mutations. | Atik T | Indian journal of pediatrics | 2016 | PMID: 26817465 |
| New Mutations Associated with Rasopathies in a Central European Population and Genotype-Phenotype Correlations. | Čizmárová M | Annals of human genetics | 2016 | PMID: 26607044 |
| The lymphatic phenotype in Noonan and Cardiofaciocutaneous syndrome. | Joyce S | European journal of human genetics : EJHG | 2016 | PMID: 26242988 |
| Nonsynonymous Single-Nucleotide Variations on Some Posttranslational Modifications of Human Proteins and the Association with Diseases. | Sun B | Computational and mathematical methods in medicine | 2015 | PMID: 26495027 |
| Myeloid Dysregulation in a Human Induced Pluripotent Stem Cell Model of PTPN11-Associated Juvenile Myelomonocytic Leukemia. | Mulero-Navarro S | Cell reports | 2015 | PMID: 26456833 |
| The first PTPN1 1 mutations in hotspot exons reported in Moroccan children with Noonan syndrome and comparison of mutation rate to previous studies. | El Bouchikhi I | Turkish journal of medical sciences | 2015 | PMID: 26084119 |
| External ear anomalies and hearing impairment in Noonan Syndrome. | van Trier DC | International journal of pediatric otorhinolaryngology | 2015 | PMID: 25862627 |
| Targeted next-generation sequencing in the diagnosis of neurodevelopmental disorders. | Okamoto N | Clinical genetics | 2015 | PMID: 25156961 |
| Clinical and Molecular Findings of Tunisian Patients with RASopathies. | Louati R | Molecular syndromology | 2014 | PMID: 25337068 |
| Molecular basis of gain-of-function LEOPARD syndrome-associated SHP2 mutations. | Yu ZH | Biochemistry | 2014 | PMID: 24935154 |
| Structure-energy-based predictions and network modelling of RASopathy and cancer missense mutations. | Kiel C | Molecular systems biology | 2014 | PMID: 24803665 |
| Behavioral profile in RASopathies. | Alfieri P | American journal of medical genetics. Part A | 2014 | PMID: 24458522 |
| Diagnosis of Noonan syndrome and related disorders using target next generation sequencing. | Lepri FR | BMC medical genetics | 2014 | PMID: 24451042 |
| MAPK activation in mature cataract associated with Noonan syndrome. | Hashida N | BMC ophthalmology | 2013 | PMID: 24219368 |
| Tegumentary manifestations of Noonan and Noonan-related syndromes. | Quaio CR | Clinics (Sao Paulo, Brazil) | 2013 | PMID: 24037001 |
| Large-scale pooled next-generation sequencing of 1077 genes to identify genetic causes of short stature. | Wang SR | The Journal of clinical endocrinology and metabolism | 2013 | PMID: 23771920 |
| IGF-I generation test in prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene. | Bertelloni S | Hormones (Athens, Greece) | 2013 | PMID: 23624134 |
| Clinical and molecular analysis of RASopathies in a group of Turkish patients. | Şimşek-Kiper PÖ | Clinical genetics | 2013 | PMID: 22420426 |
| Counteracting effects operating on Src homology 2 domain-containing protein-tyrosine phosphatase 2 (SHP2) function drive selection of the recurrent Y62D and Y63C substitutions in Noonan syndrome. | Martinelli S | The Journal of biological chemistry | 2012 | PMID: 22711529 |
| Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy. | Ezquieta B | Revista espanola de cardiologia (English ed.) | 2012 | PMID: 22465605 |
| Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome. | Bowen ME | PLoS genetics | 2011 | PMID: 21533187 |
| Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. | Jongmans MC | European journal of human genetics : EJHG | 2011 | PMID: 21407260 |
| Genotype differences in cognitive functioning in Noonan syndrome. | Pierpont EI | Genes, brain, and behavior | 2009 | PMID: 19077116 |
| Early fetal death associated with compound heterozygosity for Noonan syndrome-causative PTPN11 mutations. | Becker K | American journal of medical genetics. Part A | 2007 | PMID: 17497712 |
| A PTPN11 gene mutation (Y63C) causing Noonan syndrome is not associated with short stature in general population. | Takahashi I | The Tohoku journal of experimental medicine | 2006 | PMID: 16498234 |
| The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. | Kratz CP | Blood | 2005 | PMID: 15928039 |
| Genotype-phenotype correlations in Noonan syndrome. | Zenker M | The Journal of pediatrics | 2004 | PMID: 15001945 |
| Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. | Loh ML | Blood | 2004 | PMID: 14644997 |
| Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes. | Sarkozy A | Journal of medical genetics | 2003 | PMID: 12960218 |
| Spectrum of mutations in PTPN11 and genotype-phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome. | Musante L | European journal of human genetics : EJHG | 2003 | PMID: 12634870 |
| PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exons 3 and 13. | Maheshwari M | Human mutation | 2002 | PMID: 12325025 |
| PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome. | Kosaki K | The Journal of clinical endocrinology and metabolism | 2002 | PMID: 12161469 |
| PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. | Tartaglia M | American journal of human genetics | 2002 | PMID: 11992261 |
| Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. | Tartaglia M | Nature genetics | 2001 | PMID: 11704759 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PTPN11 | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/579af108-04e2-4cf7-9a40-35cbaa82b116 | - | - | - | - |
| https://spadahc.ciberisciii.es/variant/GRCH37/12%20112888172%20A/G | - | - | - | - |
| click to load more citations click to collapse | ||||
Conditions - Somatic
| Tumor type
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The tumor type for this variant-condition (RCV) record in ClinVar. |
Clinical impact (# of submissions)
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The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Oncogenicity
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The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the tumor type. |
Variation/condition record
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The most recent date that a submitter evaluated this variant for the tumor type. |
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Tier II (Potential)
- diagnostic
- supports diagnosis
(1)
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Sep 27, 2022 | RCV006253545.1 |
Submissions - Somatic
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Clinical impact
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The submitted somatic clinical impact for each SCV record. (Last evaluated) |
Review Status
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Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Tumor type
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The tumor type for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
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This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Tier II (Potential)
- Diagnostic
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supports diagnosis (Sep 27, 2022)
C
Contributing to aggregate classification
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criteria provided, single submitter
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Pilocytic astrocytoma |
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV007104829.1
First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025 |
Comment:
show
Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in pilocytic astrocytoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 15834506, 14644997). 3) Diagnostic significance based on multiple small studies (Evidence Level C; PMIDs: 28912153, 23817572, 19621452, 28328117). (less)
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
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Comment:
The c.188A>G (p.Tyr63Cys) variant in PTPN11 (NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys)) has been reported in the literature in at least 6 unrelated individuals and has been found to segregate with clinical features of a RASopathy in at least 15 family members (PS4, PP1_Strong; PMID: 16498234, 12634870, 12325025, 11704759). In-vitro functional studies provide some evidence that the p.Tyr63Cys variant may impact protein function (PS3; PMID: 22711529). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Tyr63Cys variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied: PP1_Strong, PS4, PS3, PM1, PP2, PP3 (Version 2.1; 09/17/2024).
Comment:
PS3, PS4, PM6, PP1, PP3, PP5
Comment:
PP1_strong, PP2, PP3, PM1, PS3_moderate
Comment:
This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes); The variant has strong previous evidence of pathogenicity in unrelated individuals with Noonan syndrome. It is a 3-star pathogenic variant in ClinVar (reviewed by the ClinGen RASopathy Variant Curation Expert Panel), and is reported in the literature in individuals with Noonan syndrome (PMIDs: 11704759; 12325025; 12634870); The variant has strong evidence for segregation with disease in multiple families (PMID: 12325025; 12634870); Variant is located in a hotspot region or cluster of pathogenic variants (N-SH2 domain; DECIPHER); Missense variant consistently predicted to be damaging by multiple in silico tools and is highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from tyrosine to cysteine; This variant is heterozygous; This gene is known to be associated with autosomal dominant disease; Both loss of function and gain of function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250), and Noonan syndrome with multiple lentigines have been associated with loss of function variants, whereas Noonan syndrome 1 (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 24935154, 21533187); Variants in this gene are known to have variable expressivity (PMID: 20301303); This variant has been shown to be maternally inherited by trio analysis.
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 63 of the PTPN11 protein (p.Tyr63Cys). This variant is present in population databases (rs121918459, gnomAD 0.006%). This missense change has been observed in individuals with Noonan syndrome (PMID: 11704759, 11992261, 12325025, 12960218, 16498234, 21407260). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13333). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PTPN11 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 22711529). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: The c.188A>G variant affects a conserved nucleotide, resulting in amino acid change from Tyr to Cys. 4/4 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is found in 1/121890 control chromosomes at a frequency of 0.0000082, which does not exceed maximal expected frequency of a pathogenic allele (0.0000625). The variant has been reported in numerous affected individuals and families in the literature and has been shown to segregate with disease in affected families. The variant is considered a common pathogenic variant. In addition, multiple reputable clinical laboratory and database classified this variant as Pathogenic. Taken together, this variant was classified as Pathogenic.
Comment:
The p.Tyr63Cys variant in PTPN11 has been reported in >40 individuals with Noona n syndrome, occurred de novo in some sporadic cases and segregated with disease in numerous families (Tartaglia 2002, Kosaki 2002, Maheshwari 2002, Musante 2003 , Loh 2004, Kratz 2005, Takahashi 2006, Becker 2007, Jongmans 2011, Simsek-Kiper 2012, LMM data). In addition, this variant has been identified as a somatic var iant in one individual with chronic myelomonocytic leukemia (CMML; Loh 2004) and as a germline variant in two individuals with both clinical features of Noonan syndrome and a malignancy (precursor B-ALL and basal cell carcinoma; Jongmans 20 11). This variant has also been identified in 1/17248 East Asian chromosomes and 1/33576 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Moreov er, the p.Tyr63Cys variant has been classified as pathogenic on April 3, 2018 by the ClinGen-approved RASopathy Expert Panel (ClinVar SCV000616372.1). In summar y, this variant meets criteria to be classified as pathogenic for Noonan syndrom e in an autosomal dominant manner based upon presence in multiple affected indiv iduals, de novo occurrences and segregation studies. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM6_Strong.
Comment:
[ACMG/AMP/ClinGen RASopathy: PS1, PS3, PS4, PP1_Strong, PM1, PP2, PP3] This alteration has an amino acid change previously established as pathogenic (regardless of nucleotide change) [PS1], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], has a prevalence that is significantly increased compared with controls (RR/OR > 5; CI does not include 1.0) [PS4], has been shown to cosegregate with disease in multiple affected family members [PP1_Strong], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3].
Comment:
PS3, PM1, PM2, PP2, PP3, PP5
Comment:
This is a missense alteration in which an A is replaced by a G at coding nucleotide 188 and is predicted to change a Tyrosine to a Cysteine at amino acid codon 63. Classification criteria: PS1, PS3, PM1, PM2, PP3.
Comment:
This variant has been reported in the literature in at least 10 individuals with a clinical diagnosis or suspicion of Noonan syndrome, segregating with disease in more than 15 affected family members (Selected publications: Maheshwari 2002 PMID:12325025; Musante 2003 PMID:12634870; Jongmans 2011 PMID:21407260; Athota 2020 PMID:32164556). This variant is present in 0.005% (1/18394) of East Asian alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/12-112888172-A-G?dataset=gnomad_r2_1). Please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with many laboratories and the ClinGen RASopathy Variant Curation Expert Panel classifying it as pathogenic (Variation ID:13333). This variant is located at a residue directly involved in interactions between N-SH2 and PTPN domains (Gelb 2018 PMID:29493581). An in vitro functional study showed that this variant impacts protein structure, resulting in increased protein activity (Martinelli 2012 PMID:22711529). However, this study study may not accurately represent in vivo biological function. PTPN11 has a low rate of benign missense variation and pathogenic missense variation is common (Gelb 2018 PMID:29493581). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In summary, this variant is classified as pathogenic
Comment:
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 22711529). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.95 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.96 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013333 /PMID: 11704759).The variant has been previously reported as de novo in a similarly affected individual (3billion dataset).The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 11704759, 12325025, 12634870, 16498234). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in pilocytic astrocytoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 15834506, 14644997). 3) Diagnostic significance based on multiple small studies (Evidence Level C; PMIDs: 28912153, 23817572, 19621452, 28328117).
Comment:
PTPN11 c.188A>G p.(Tyr63Cys) variant has been classified as pathogenic by the ClinGen RASopathy Variant Curation Expert Panel (ClinVar accession: VCV000013333.85, PMID: 29493581).
Comment:
This is a nonsynonymous variant in the PTPN11 gene (OMIM: 176876). Pathogenic variants in this gene have been associated with autosomal dominant Noonan syndrome 1. This variant has been reported in at least 15 unrelated affected individuals (PMID: 16498234, 12634870, 12325025, 11704759) (PS4_Moderate) and it has been observed to segregate with disease in at least 10 individuals from multiple families (PMID: 11704759, 11992261, 21407260) (PP1). Functional studies have shown that this variant alters PTPN11 protein function (PMID: 22711529) (PS3) and multiple computational algorithms predict a deleterious effect for this variant (REVEL score: 0.955) (PP3). Moreover, this variant lies within a known hotspot for pathogenic variants or a well-established critical functional domain of the PTPN11 protein (PMID: 29493581) (PM1). It has a 0.0022% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on the evidence, this variant is classified as pathogenic for autosomal dominant Noonan syndrome 1. Inheritance from an unaffected or mildly affected parent has been reported, consistent with incomplete penetrance and variable expressivity (PMID: 22465605, 22465605).
Comment:
NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys) is a missense variant that results in the substitution of tyrosine with cysteine. The affected residue or protein region has prior evidence supporting clinical relevance. Segregation evidence has been reported in affected families. Functional evidence supports a deleterious effect on the gene or gene product (PMID: 22711529; PMID: 12634870; PMID: 12325025; PMID: 32164556; PMID: 16498234). This variant has been recurrently observed in individuals with related phenotype (PMID: 22711529; PMID: 12634870; PMID: 12325025; PMID: 32164556; PMID: 16498234). Multiple computational predictions support a deleterious effect on the gene or gene product. Based on the available data, this variant is classified as pathogenic.
Comment:
PTPN11: PP1:Strong, PS2, PS4, PM1, PM2, PP2, PP3, PS3:Supporting
Comment:
Published functional studies demonstrate that Y63C perturbs the autoinhibitory interaction between the N-SH2 and protein-tyrosine phosphatase domains, which is required to maintain SHP2 in its catalytically inactive state (Martinelli et al., 2012); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21407260, 12325025, 24803665, 11704759, 30055033, 30417923, 32164556, 24219368, 22711529, 12634870, 26242988, 25156961, 30692697, 30050098, 29907801, 31219622, 31560489, 32371413, 32901917, 11992261, 9491886, 16053901, 29493581)
Comment:
ACMG classification criteria: PS3 strong, PS4 strong, PM1 moderated, PP1 strong, PP2 supporting, PP3 supporting
Comment:
This variant has been previously reported as a heterozygous change in patients with PTPN11-related disorders (PMID: 16498234, 12634870, 12325025, 11704759, 21407260). Functional studies suggest that this variant impacts protein structure, resulting in increased protein activity (PMID: 22711529). The c.188A>G (p.Tyr63Cys) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/251010) and thus is presumed to be rare. Based on the available evidence, the c.188A>G (p.Tyr63Cys) variant is classified as Pathogenic.
Comment:
The PTPN11 c.188A>G; p.Tyr63Cys variant (rs121918459) has been reported in multiple patients diagnosed with Noonan syndrome (Tartaglia 2001, Jongmans 2011, Martinelli 2012, Hashida 2013, Lepri 2014, Okamoto 2015). This variant is found on only three chromosomes (3/251010 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism, and it is listed as pathogenic in ClinVar by multiple clinical laboratories (Variation ID: 13333). The p.Tyr63Cys variant is located in a structurally important region of the catalytic N-terminal SH2 domain of PTPN11 (Hof 1998), and several additional variants in neighboring codons (p.Asp61Asn, p.Asp61Gly, p.Tyr62Asp, p.Tyr62Asn) have also been identified in individuals with Noonan syndrome (Jongmans 2011, Tartaglia 2002, Tartaglia 2006). Functional characterization of the p.Tyr63Cys variant protein indicates over-activation of p38alpha MAP kinase and phosphorERK1/2 upon growth factor signaling (Martinelli 2012, Hashida 2013), consistent with the established disease mechanisms of Noonan syndrome. Based on available information, the p.Tyr63Cys variant is classified as pathogenic. References: Hashida N et al. MAPK activation in mature cataract associated with Noonan syndrome. BMC Ophthalmol. 2013 Nov 12;13:70. PMID: 24219368 Hof P et al. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998 Feb 20;92(4):441-50. PMID: 9491886 Jongmans M et al. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet. 2011 Aug;19(8):870-4. PMID: 21407260 Lepri et al. Diagnosis of Noonan syndrome and related disorders using target next generation sequencing. BMC Med Genet. 2014 Jan 23;15:14. PMID: 24451042 Martinelli S et al. Counteracting effects operating on Src homology 2 domain-containing protein-tyrosine phosphatase 2 (SHP2) function drive selection of the recurrent Y62D and Y63C substitutions in Noonan syndrome. J Biol Chem. 2012 Aug 3;287(32):27066-77. PMID: 22711529 Okamoto N et al. Targeted next-generation sequencing in the diagnosis of neurodevelopmental disorders. Clin Genet. 2015 Sep;88(3):288-92. PMID: 25156961 Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001 Dec;29(4):465-8. PMID: 11704759 Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 Jun;70(6):1555-63. PMID: 11992261 Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 Feb;78(2):279-90. PMID: 16358218
Comment:
ACMG Criteria: PS1, PS3, PS4, PM1, PM2_P, PP1, PP3, PP5; Variant was found in heterozygous state
Comment:
PS4, PP1_strong, PM1, PS3_supporting, PP2, PP3 c.188A>G, located in exon 3 of the PTPN11 gene, is predicted to result in the substitution of tyrosine by cysteine at codon 63, p.(Tyr63Cys). This variant is found in 3/236472 alleles at a frequency of 0.001% in the gnomAD v2.1.1 database, non-cancer dataset. It has been observed in multiple affected individuals (PMID: 16498234, 12634870, 12325025, 11704759) (PS4, PP1_strong). This position affects a (potentially) clinically important functional domain (PM1). PTPN11 gene has a low rate of benign missense variants (PP2). The SpliceAI algorithm predicts no significant impact on splicing. The REVEL meta-predictor score for this variant (0.984) suggests a deleterious effect on protein function according to Pejaver 2022 thresholds (PMID: 36413997) (PP3). In vitro functional assays suggest that the p.Tyr63Cys variant could affect the protein's function (PMID:22711529) (PS3_supporting). This variant has been reported in the ClinVar database (46x pathogenic, 1x likely pathogenic), and in the LOVD database (21x likely pathogenic, 5x pathogenic), furthermore, it has been classified by the ClinGen RASopathy Variant Curation Expert Panel as pathogenic. Based on currently available information, the variant c.188A>G should be considered a pathogenic variant.
Comment:
The gene PTPN11 has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 3.13. The gene PTPN11 contains 144 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. (PP2 - Supporting) | 28 variants within 6 amino acid positions of the variant p.Tyr63Cys have been shown to be pathogenic, while none have been shown to be benign. (PM1 - Moderate) | The p.Tyr63Cys missense variant is predicted to be damaging by both SIFT and PolyPhen2. The tyrosine residue at codon 63 of PTPN11 is conserved in all mammalian species. The nucleotide c.188 in PTPN11 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. (PP3 - Supporting) | Functional studies demonstrate that this variant has a damaging effect on the gene or gene product (PS3 - Strong) | The variant cosegregates with the disease in multiple affected family members. (PP1_Strong - Strong)
Comment:
Variant classified using ACMG guidelines
Comment:
The PTPN11 c.188A>G variant is predicted to result in the amino acid substitution p.Tyr63Cys. This variant has been reported in many unrelated individuals with Noonan syndrome and was found to occur de novo in several cases and segregated with disease in many families (Tartaglia et al. 2001. PubMed ID: 11704759; Maheshwari et al. 2002. PubMed ID: 12325025; Jongmans et al. 2011. PubMed ID: 21407260; Okamoto et al. 2015. PubMed ID: 25156961). Functional studies indicate that the p.Tyr63Cys variant alters the functional regulation of SHP2 protein by affecting the stability between N-SH2 and PTP domains (Martinelli et al. 2012. PubMed ID: 22711529). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic.
Comment:
The missense c.188A>G(p.Tyr63Cys) variant in PTPN11 gene has been reported previously in heterozygous state in individual(s) affected with Noonan syndrome (Takahashi et al., 2006). Experimental studies have shown that this missense change affects PTPN11 function (Martinelli S et al., 2012). This variant is reported with the allele frequency of 0.001% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. The amino acid Tyr at position 63 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Tyr63Cys in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic.
Citations for somatic classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Comprehensive Genomic Profiling of 282 Pediatric Low- and High-Grade Gliomas Reveals Genomic Drivers, Tumor Mutational Burden, and Hypermutation Signatures. | Johnson A | The oncologist | 2017 | PMID: 28912153 |
| Noonan syndrome, PTPN11 mutations, and brain tumors. A clinical report and review of the literature. | Siegfried A | American journal of medical genetics. Part A | 2017 | PMID: 28328117 |
| Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. | Jones DT | Nature genetics | 2013 | PMID: 23817572 |
| Pilocytic astrocytoma in a child with Noonan syndrome. | Schuettpelz LG | Pediatric blood & cancer | 2009 | PMID: 19621452 |
| Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia. | Niihori T | Journal of human genetics | 2005 | PMID: 15834506 |
| Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. | Loh ML | Blood | 2004 | PMID: 14644997 |
Text-mined citations for rs121918459 ...
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Record last updated Aug 08, 2026
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.