VCV000804174.9 - ClinVar

NM_002834.5(PTPN11):c.762ACA[2] (p.Gln257del)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Likely pathogenic (1); Uncertain significance (2)

3 out of 5 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002834.5(PTPN11):c.762ACA[2] (p.Gln257del)

Variation ID: 804174 Accession: VCV000804174.9

Type and length

Microsatellite, 3 bp

Location

Cytogenetic: 12q24.13 12: 112472949-112472951 (GRCh38) [ NCBI UCSC ] 12: 112910753-112910755 (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	Jan 11, 2020	Feb 15, 2026	Aug 20, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_002834.5:c.762ACA[2] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002825.3:p.Gln257del	inframe deletion
NM_002834.5:c.768_770del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001330437.2:c.762ACA[2]	NP_001317366.1:p.Gln257del	inframe deletion
NM_001374625.1:c.759ACA[2]	NP_001361554.1:p.Gln256del	inframe deletion
NM_002834.3:c.768_770del
NM_002834.4:c.768_770delACA
NM_080601.3:c.762ACA[2]	NP_542168.1:p.Gln257del	inframe deletion
NC_000012.12:g.112472949ACA[2]
NC_000012.11:g.112910753ACA[2]
NG_007459.1:g.59218ACA[2]
LRG_614:g.59218ACA[2]
LRG_614t1:c.768_770del

... more HGVS ... less HGVS

Protein change

Q257del, Q256del

Other names

Canonical SPDI

NC_000012.12:112472948:ACAACAACA:ACAACA

Global minor allele frequency (GMAF) Help The 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.

Links

ClinGen: CA607379398 dbSNP: rs397507524 VarSome

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
Gene	OMIM	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.
Noonan syndrome 1	Uncertain significance (1)	no assertion criteria provided	Dec 19, 2019	RCV000991102.1
RASopathy	Uncertain significance (1)	criteria provided, single submitter	Aug 20, 2025	RCV002549756.5
Juvenile myelomonocytic leukemia LEOPARD syndrome 1 Metachondromatosis Noonan syndrome 1	Uncertain significance (1)	criteria provided, single submitter	Nov 15, 2021	RCV002489463.1
not provided	Likely pathogenic (1)	criteria provided, single submitter	Dec 13, 2022	RCV003229002.1
PTPN11-related disorder	Uncertain significance (1)	no assertion criteria provided	Feb 11, 2024	RCV004544990.2

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.
Uncertain significance (Nov 15, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	LEOPARD syndrome 1 Metachondromatosis Noonan syndrome 1 Juvenile myelomonocytic leukemia	Fulgent Genetics, Fulgent Genetics Accession: SCV002778870.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Likely pathogenic (Dec 13, 2022) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV003926424.1 First in ClinVar: May 27, 2023 Last updated: May 27, 2023	Comment: show Published functional studies demonstrate that the Q257del variant enhances phosphatase activation/phosphorylation under the influence of the activating BTAM peptide in E.coli and EGF stimulation in HEK293 cells but not independently (Martinelli et al., 2020); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32112654, 9491886, 11992261, 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

Uncertain significance (Aug 20, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	RASopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002938004.4 First in ClinVar: Feb 07, 2023 Last updated: Feb 15, 2026	Publications: PubMed (1) PubMed: 32112654 Comment: show This variant, c.768_770del, results in the deletion of 1 amino acid(s) of the PTPN11 protein (p.Gln257del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has been observed in individual(s) with Noonan syndrome (PMID: 32112654). ClinVar contains an entry for this variant (Variation ID: 804174). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects PTPN11 function (PMID: 32112654). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (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

Uncertain significance (Dec 19, 2019) N Not contributing to aggregate classification	no assertion criteria provided	Noonan syndrome 1	Department of Human Genetics, University Hospital Magdeburg Accession: SCV001132049.1 First in ClinVar: Jan 11, 2020 Last updated: Jan 11, 2020	Comment: show We found the variant in an affected girl. Her father also carries the variant, but is not affected. However, Noonan syndrome may be subtle in adults and clinical variation within families has been described. Two alleles were reported in gnomAD (AF 8.081e-6). Biochemical and functional studies show an activating effect, but not as strongly as for the Q257dup mutation. (less) Observation: 1 Collection method: clinical testing Allele origin: paternal Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: paternal Affected status: yes Zygosity: 1 Single Heterozygote

Uncertain significance (Feb 11, 2024) N Not contributing to aggregate classification	no assertion criteria provided	PTPN11-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV004771700.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: show The PTPN11 c.768_770delACA variant is predicted to result in an in-frame deletion (p.Gln257del). This variant was observed in an individual with a clinical diagnosis of Noonan syndrome, but was also observed in a parent and grandparent with no obvious or known features of Noonan syndrome (Martinelli et al. 2020. PubMed ID: 32112654). In the same study, the variant led to a mild activating effect using functional studies. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (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

Comment:

Published functional studies demonstrate that the Q257del variant enhances phosphatase activation/phosphorylation under the influence of the activating BTAM peptide in E.coli and EGF stimulation in HEK293 cells but not independently (Martinelli et al., 2020); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32112654, 9491886, 11992261, 16053901, 29493581)

Comment:

This variant, c.768_770del, results in the deletion of 1 amino acid(s) of the PTPN11 protein (p.Gln257del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has been observed in individual(s) with Noonan syndrome (PMID: 32112654). ClinVar contains an entry for this variant (Variation ID: 804174). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects PTPN11 function (PMID: 32112654). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

We found the variant in an affected girl. Her father also carries the variant, but is not affected. However, Noonan syndrome may be subtle in adults and clinical variation within families has been described. Two alleles were reported in gnomAD (AF 8.081e-6). Biochemical and functional studies show an activating effect, but not as strongly as for the Q257dup mutation.

Comment:

The PTPN11 c.768_770delACA variant is predicted to result in an in-frame deletion (p.Gln257del). This variant was observed in an individual with a clinical diagnosis of Noonan syndrome, but was also observed in a parent and grandparent with no obvious or known features of Noonan syndrome (Martinelli et al. 2020. PubMed ID: 32112654). In the same study, the variant led to a mild activating effect using functional studies. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Pathogenic PTPN11 variants involving the poly-glutamine Gln(255) -Gln(256) -Gln(257) stretch highlight the relevance of helix B in SHP2's functional regulation.	Martinelli S	Human mutation	2020	PMID: 32112654

Text-mined citations for rs397507524 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Apr 13, 2026