The Gly12Cys variant in HRAS has been reported in the literature in six individu als with severe neonatal Costello syndrome (Kerr 2006, Lo 2008, Lin 2009, Niihor i 2011, Lorenz 2012). This variant has been reported to have occurred de novo in one proband (Lorenz 2012). Several other DNA variants affecting codon 12 of HRA S are commonly observed in patients with Costello syndrome (Niihori 2011). There fore, this variant is highly likely to be pathogenic.
NM_005343.4(HRAS):c.34G>T (p.Gly12Cys)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic
Pathogenic (13)
Pathogenic (13)
13 out of 17 submissions contributed to this classification
Help
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.
17
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_005343.4(HRAS):c.34G>T (p.Gly12Cys)
Variation ID: 12613 Accession: VCV000012613.63
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p15.5 11: 534289 (GRCh38) [ NCBI UCSC ] 11: 534289 (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 16, 2015 Jun 20, 2026 Nov 28, 2025 Somatic - Clinical impact Nov 22, 2025 Nov 22, 2025 Aug 2, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005343.4:c.34G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005334.1:p.Gly12Cys missense NM_176795.5:c.34G>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_789765.1:p.Gly12Cys missense NM_001130442.3:c.34G>T NP_001123914.1:p.Gly12Cys missense NM_001318054.2:c.-286G>T 5 prime UTR NC_000011.10:g.534289C>A NC_000011.9:g.534289C>A NG_007666.1:g.6262G>T LRG_506:g.6262G>T LRG_506t1:c.34G>T LRG_506p1:p.Gly12Cys P01112:p.Gly12Cys - Protein change
- G12C
- Other names
-
p.G12C:GGC>TGC
- Canonical SPDI
- NC_000011.10:534288:C:A
-
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.
- -
- 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. |
|||
| HRAS | No evidence available | No evidence available |
GRCh38 GRCh38 GRCh37 |
11 | 788 | |
| LRRC56 | - | - |
GRCh38 GRCh38 GRCh37 |
488 | 1266 | |
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 (8) |
criteria provided, multiple submitters, no conflicts
|
Nov 28, 2025 | RCV000013447.49 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jun 10, 2012 | RCV000029211.11 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jun 10, 2012 | RCV000032851.11 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV000149829.5 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Oct 6, 2023 | RCV000212495.42 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 31, 2018 | RCV000762849.6 |
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
(Oct 31, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Malignant tumor of urinary bladder
Large congenital melanocytic nevus Epidermal nevus Linear nevus sebaceous syndrome Thyroid cancer, nonmedullary, 2 Costello syndrome |
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893209.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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
(Nov 20, 2012)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Costello syndrome
(Autosomal dominant inheritance)
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000062132.5
First in ClinVar: May 03, 2013 Last updated: Apr 30, 2017 |
Comment:
show
The Gly12Cys variant in HRAS has been reported in the literature in six individu als with severe neonatal Costello syndrome (Kerr 2006, Lo 2008, Lin 2009, Niihor i 2011, Lorenz 2012). This variant has been reported to have occurred de novo in one proband (Lorenz 2012). Several other DNA variants affecting codon 12 of HRA S are commonly observed in patients with Costello syndrome (Niihori 2011). There fore, this variant is highly likely to be pathogenic. (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: 1
|
|
|
Pathogenic
(Aug 14, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Blueprint Genetics
Accession: SCV000927854.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019
Comment:
Patient analyzed with Noonan Syndrome Panel
|
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 09, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Costello syndrome |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001448594.1
First in ClinVar: Dec 07, 2020 Last updated: Dec 07, 2020 |
Comment:
show
Variant summary: HRAS c.34G>T (p.Gly12Cys) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250294 control chromosomes (gnomAD). c.34G>T has been reported in the literature in multiple individuals affected with Costello Syndrome (e.g. Niihori_2011, McCormick_2013, Choi_2019). These data indicate that the variant is very likely to be associated with disease. In functional studies, Niihori et al (Niihori_2011) report that there was an increase in guanosine triphosphate (GTP)-bound HRAS and activation of RAS signaling pathway (as measured by the activation of ELK1 and c-Jun) in cells transfected with the variant of interest. In addition, HGMD database reports several other missense variants affecting the same codon and nearby codons (e.g. p.G12R, p.G12S, p.G12V, p.G12A, p.G13D, p.G13C) suggesting this area might be a mutational hotspot. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the 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
(Sep 21, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Costello syndrome
(Autosomal dominant inheritance)
|
Breda Genetics srl, Breda Genetics srl
Accession: SCV002587819.1
First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022 |
Comment:
show
The variant in c.34G>T (p.Gly12Cys) in HRAS gene is reported as pathogenic for Costello syndrome and other HRAS-related diseases in ClinVar (Variation ID: 12613) and in the Global Variome shared LOVD database v.3.0 (genomic variant: #0000345686). There is no information on frequency in gnomAD or 1000 Genomes Project. The variant has been reported in in multiple individuals affected with Costello Syndrome (Choi et al., 2019, PMID: 31394527; McCormick et al., 2013, PMID: 23429430; Niihori et al., 2011, PMID: 21850009). (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
Zygosity: 1 Single Heterozygote
|
|
|
Pathogenic
(Mar 10, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
GeneDx
Accession: SCV000207843.14
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
show
Published functional studies of the G12C variant have shown that it results in increased active, GTP-bound HRAS (Niihori et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 16443854, 24224811, 23093928, 24803665, 31394527, 22926243, 21850009, 16155195, 18039947, 33258288, 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
(Oct 06, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004562717.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
show
The HRAS c.34G>T; p.Gly12Cys variant (rs104894229; ClinVar Variation ID: 12613) is reported in the literature as a recurrent de novo variant in multiple individuals affected with Costello syndrome (Choi 2019, Kerr 2006, Lorenz 2012). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine residues at codons 12 and 13 are frequently altered in both Costello syndrome patients (Aoki 2005, Estep 2006, Gripp 2005, Kerr 2006, Niihori 2011). Functional characterization of the p.Gly12Cys protein indicates increased downstream MEK signaling activity (Niihori 2011), consistent with the established disease mechanism of Costello syndrome. Based on available information, this variant is considered to be pathogenic. References: Choi N et al. Phenotypic and Genetic Characteristics of Five Korean Patients with Costello Syndrome. Cytogenet Genome Res. 2019;158(4):184-191. PMID: 31394527. Kerr B et al. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J Med Genet. 2006 May;43(5):401-5. PMID: 16443854 Lorenz S et al Two cases with severe lethal course of Costello syndrome associated with HRAS p.G12C and p.G12D. Eur J Med Genet. 2012 Nov;55(11):615-9. PMID: 22926243. Niihori T et al. HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome. J Hum Genet. 2011 Oct;56(10):707-15. PMID: 21850009. (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
(Jul 09, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Costello syndrome |
Institute of Immunology and Genetics Kaiserslautern
Accession: SCV005093867.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
show
ACMG Criteria:PP3, PP5, PM2_P, PM1, PM5, PS3; 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:
Skeletal dysplasia (present) , Ventricular septal hypertrophy (present) , Ventricular tachycardia (present) , Hypotonia (present) , Hypertelorism (present) , Deeply set eye (present) , Low-set ears (present) , Downslanted palpebral fissures (present) , Retrognathia (present) , Broad thumb (present) , Polyhydramnios (present)
|
|
|
Pathogenic
(Jun 04, 2014)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Costello syndrome |
Molecular Diagnostics Lab, Nemours Children's Health, Delaware
Accession: SCV000263053.2
First in ClinVar: Oct 11, 2015 Last updated: Apr 13, 2025 |
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 1
Clinical Features:
History of polyhydramnios (present) , Poor respiratory effort (present) , Hypotonia (present) , Dysmorphic features suggestive of Costello syndrome (present) , Normal karyotype on amnio (present)
Age: 0-9 years
Sex: female
|
|
|
Pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Malignant tumor of urinary bladder
Costello syndrome Epidermal nevus Linear nevus sebaceous syndrome Large congenital melanocytic nevus Thyroid cancer, nonmedullary, 2
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. |
Juno Genomics, Hangzhou Juno Genomics, Inc
Accession: SCV005418623.2
First in ClinVar: Nov 30, 2024 Last updated: Oct 05, 2025 |
Comment:
show
Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.;De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.;Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc).;Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. (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
(Feb 03, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Costello syndrome |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003253337.4
First in ClinVar: Feb 07, 2023 Last updated: Mar 07, 2026 |
Comment:
show
This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 12 of the HRAS protein (p.Gly12Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Costello syndrome (PMID: 16443854, 18039947, 22926243). ClinVar contains an entry for this variant (Variation ID: 12613). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HRAS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HRAS function (PMID: 21850009). This variant disrupts the p.Gly12 amino acid residue in HRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16170316, 16372351, 16443854, 16835863, 17601930, 18042262, 21850009, 22420426, 28027064). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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
(Feb 01, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247463.38
First in ClinVar: May 09, 2020 Last updated: Jun 20, 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: 2
|
|
|
Pathogenic
(Nov 28, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Costello syndrome |
The Central Laboratory of Birth Defects Prevention and Control, The Affiliated Women and Children's Hospital of Ningbo University
Accession: SCV007126570.2
First in ClinVar: Dec 20, 2025 Last updated: Jun 20, 2026 |
Comment:
show
The NM_176795.5 c.34G>T is a missense variant in HRAS gene.Not observed at significant frequency in large population cohorts (gnomAD). This variant has been reported in the literature in multiple individuals affected with Costello Syndrome (PMID 31394527, 22926243, 24637993, 21850009). The c.34G>T variant in the HRAS gene of the tested sample was confirmed to be a de novo variant through parental sample verification. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.788). At the same base site, it leads to another amino acid variant c.34G>A (p.Gly12Ser), which has been confirmed to be pathogenic. This variant has been reported in ClinVar as pathogenic (Accession: VCV000012613.62). Based on the available evidence, this alteration is classified as pathogenic. (less)
Observation 1
Collection method: clinical testing
Allele origin: de novo
Affected status: yes
Sex: male
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Rasopathy |
Baylor Genetics
Accession: SCV000196673.1
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
|
|
|
Pathogenic
(Jun 10, 2012)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
COSTELLO SYNDROME |
OMIM
Accession: SCV000033694.6
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Observation: 1
Collection method: literature only
Allele origin: unknown
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: unknown
Affected status: not provided
Comment on evidence:
Costello Syndrome In a male infant with severe Costello syndrome (218040), Lo et al. (2008) identified a 34G-T transversion in the HRAS gene, resulting in … (more)
Costello Syndrome In a male infant with severe Costello syndrome (218040), Lo et al. (2008) identified a 34G-T transversion in the HRAS gene, resulting in a gly12-to-cys (G12C) substitution. The patient developed respiratory distress after delivery and required intubation and ventilatory support secondary to small lungs and upper airway obstruction. He had an atrial tachyarrhythmia with apparent thickening of the myocardial wall and redundant mitral valve tissue on echocardiogram, and had echogenic kidneys with thick-walled pelvises on ultrasound. He died at 3 months of age due to respiratory failure. Nevus Sebaceous, Somatic Groesser et al. (2012) identified a somatic G12C mutation in 1 (2%) of 65 nevus sebaceous tumors (see 162900). Epidermal Nevus, Somatic Hafner et al. (2012) identified a somatic G12C mutation in 1 of 72 keratinocytic epidermal nevi (162900). (less)
|
|
|
Pathogenic
(Jun 10, 2012)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
NEVUS SEBACEOUS, SOMATIC |
OMIM
Accession: SCV000051857.6
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Observation: 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Comment on evidence:
Costello Syndrome In a male infant with severe Costello syndrome (218040), Lo et al. (2008) identified a 34G-T transversion in the HRAS gene, resulting in … (more)
Costello Syndrome In a male infant with severe Costello syndrome (218040), Lo et al. (2008) identified a 34G-T transversion in the HRAS gene, resulting in a gly12-to-cys (G12C) substitution. The patient developed respiratory distress after delivery and required intubation and ventilatory support secondary to small lungs and upper airway obstruction. He had an atrial tachyarrhythmia with apparent thickening of the myocardial wall and redundant mitral valve tissue on echocardiogram, and had echogenic kidneys with thick-walled pelvises on ultrasound. He died at 3 months of age due to respiratory failure. Nevus Sebaceous, Somatic Groesser et al. (2012) identified a somatic G12C mutation in 1 (2%) of 65 nevus sebaceous tumors (see 162900). Epidermal Nevus, Somatic Hafner et al. (2012) identified a somatic G12C mutation in 1 of 72 keratinocytic epidermal nevi (162900). (less)
|
|
|
Pathogenic
(Jun 10, 2012)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
EPIDERMAL NEVUS, SOMATIC |
OMIM
Accession: SCV000056620.6
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Observation: 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: somatic
Affected status: not provided
Comment on evidence:
Costello Syndrome In a male infant with severe Costello syndrome (218040), Lo et al. (2008) identified a 34G-T transversion in the HRAS gene, resulting in … (more)
Costello Syndrome In a male infant with severe Costello syndrome (218040), Lo et al. (2008) identified a 34G-T transversion in the HRAS gene, resulting in a gly12-to-cys (G12C) substitution. The patient developed respiratory distress after delivery and required intubation and ventilatory support secondary to small lungs and upper airway obstruction. He had an atrial tachyarrhythmia with apparent thickening of the myocardial wall and redundant mitral valve tissue on echocardiogram, and had echogenic kidneys with thick-walled pelvises on ultrasound. He died at 3 months of age due to respiratory failure. Nevus Sebaceous, Somatic Groesser et al. (2012) identified a somatic G12C mutation in 1 (2%) of 65 nevus sebaceous tumors (see 162900). Epidermal Nevus, Somatic Hafner et al. (2012) identified a somatic G12C mutation in 1 of 72 keratinocytic epidermal nevi (162900). (less)
|
|
Comment:
Comment:
Variant summary: HRAS c.34G>T (p.Gly12Cys) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250294 control chromosomes (gnomAD). c.34G>T has been reported in the literature in multiple individuals affected with Costello Syndrome (e.g. Niihori_2011, McCormick_2013, Choi_2019). These data indicate that the variant is very likely to be associated with disease. In functional studies, Niihori et al (Niihori_2011) report that there was an increase in guanosine triphosphate (GTP)-bound HRAS and activation of RAS signaling pathway (as measured by the activation of ELK1 and c-Jun) in cells transfected with the variant of interest. In addition, HGMD database reports several other missense variants affecting the same codon and nearby codons (e.g. p.G12R, p.G12S, p.G12V, p.G12A, p.G13D, p.G13C) suggesting this area might be a mutational hotspot. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The variant in c.34G>T (p.Gly12Cys) in HRAS gene is reported as pathogenic for Costello syndrome and other HRAS-related diseases in ClinVar (Variation ID: 12613) and in the Global Variome shared LOVD database v.3.0 (genomic variant: #0000345686). There is no information on frequency in gnomAD or 1000 Genomes Project. The variant has been reported in in multiple individuals affected with Costello Syndrome (Choi et al., 2019, PMID: 31394527; McCormick et al., 2013, PMID: 23429430; Niihori et al., 2011, PMID: 21850009).
Comment:
Published functional studies of the G12C variant have shown that it results in increased active, GTP-bound HRAS (Niihori et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 16443854, 24224811, 23093928, 24803665, 31394527, 22926243, 21850009, 16155195, 18039947, 33258288, 29493581)
Comment:
The HRAS c.34G>T; p.Gly12Cys variant (rs104894229; ClinVar Variation ID: 12613) is reported in the literature as a recurrent de novo variant in multiple individuals affected with Costello syndrome (Choi 2019, Kerr 2006, Lorenz 2012). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine residues at codons 12 and 13 are frequently altered in both Costello syndrome patients (Aoki 2005, Estep 2006, Gripp 2005, Kerr 2006, Niihori 2011). Functional characterization of the p.Gly12Cys protein indicates increased downstream MEK signaling activity (Niihori 2011), consistent with the established disease mechanism of Costello syndrome. Based on available information, this variant is considered to be pathogenic. References: Choi N et al. Phenotypic and Genetic Characteristics of Five Korean Patients with Costello Syndrome. Cytogenet Genome Res. 2019;158(4):184-191. PMID: 31394527. Kerr B et al. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J Med Genet. 2006 May;43(5):401-5. PMID: 16443854 Lorenz S et al Two cases with severe lethal course of Costello syndrome associated with HRAS p.G12C and p.G12D. Eur J Med Genet. 2012 Nov;55(11):615-9. PMID: 22926243. Niihori T et al. HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome. J Hum Genet. 2011 Oct;56(10):707-15. PMID: 21850009.
Comment:
ACMG Criteria:PP3, PP5, PM2_P, PM1, PM5, PS3; Variant was found in heterozygous state
Comment:
Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.;De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.;Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc).;Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 12 of the HRAS protein (p.Gly12Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Costello syndrome (PMID: 16443854, 18039947, 22926243). ClinVar contains an entry for this variant (Variation ID: 12613). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HRAS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HRAS function (PMID: 21850009). This variant disrupts the p.Gly12 amino acid residue in HRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16170316, 16372351, 16443854, 16835863, 17601930, 18042262, 21850009, 22420426, 28027064). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in embryonal rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 6092966, 24224811). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 34166060, 24436047, 2680062, 19681119, 24332040, 25768946).
Comment:
The NM_176795.5 c.34G>T is a missense variant in HRAS gene.Not observed at significant frequency in large population cohorts (gnomAD). This variant has been reported in the literature in multiple individuals affected with Costello Syndrome (PMID 31394527, 22926243, 24637993, 21850009). The c.34G>T variant in the HRAS gene of the tested sample was confirmed to be a de novo variant through parental sample verification. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.788). At the same base site, it leads to another amino acid variant c.34G>A (p.Gly12Ser), which has been confirmed to be pathogenic. This variant has been reported in ClinVar as pathogenic (Accession: VCV000012613.62). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
Variant classified using ACMG guidelines
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Phenotypic and Genetic Characteristics of Five Korean Patients with Costello Syndrome. | Choi N | Cytogenetic and genome research | 2019 | PMID: 31394527 |
| Novel pathogenic variant in the HRAS gene with lethal outcome and a broad phenotypic spectrum among Polish patients with Costello syndrome. | Pelc M | Clinical dysmorphology | 2017 | PMID: 28027064 |
| Uniparental Trisomy of a Mutated HRAS Proto-Oncogene in Embryonal Rhabdomyosarcoma of a Patient With Costello Syndrome. | Menke J | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2015 | PMID: 24637993 |
| Assessing genotype-phenotype correlation in Costello syndrome using a severity score. | McCormick EM | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 23429430 |
| Clinical and molecular analysis of RASopathies in a group of Turkish patients. | Şimşek-Kiper PÖ | Clinical genetics | 2013 | PMID: 22420426 |
| Two cases with severe lethal course of Costello syndrome associated with HRAS p.G12C and p.G12D. | Lorenz S | European journal of medical genetics | 2012 | PMID: 22926243 |
| Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome. | Groesser L | Nature genetics | 2012 | PMID: 22683711 |
| Keratinocytic epidermal nevi are associated with mosaic RAS mutations. | Hafner C | Journal of medical genetics | 2012 | PMID: 22499344 |
| HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome. | Niihori T | Journal of human genetics | 2011 | PMID: 21850009 |
| Prenatal features of Costello syndrome: ultrasonographic findings and atrial tachycardia. | Lin AE | Prenatal diagnosis | 2009 | PMID: 19382114 |
| Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome. | Schulz AL | Clinical genetics | 2008 | PMID: 18042262 |
| Severe neonatal manifestations of Costello syndrome. | Lo IF | Journal of medical genetics | 2008 | PMID: 18039947 |
| De novo HRAS and KRAS mutations in two siblings with short stature and neuro-cardio-facio-cutaneous features. | Søvik O | Journal of medical genetics | 2007 | PMID: 17601930 |
| Paternal bias in parental origin of HRAS mutations in Costello syndrome. | Sol-Church K | Human mutation | 2006 | PMID: 16835863 |
| Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. | Kerr B | Journal of medical genetics | 2006 | PMID: 16443854 |
| HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy. | Estep AL | American journal of medical genetics. Part A | 2006 | PMID: 16372351 |
| Germline mutations in HRAS proto-oncogene cause Costello syndrome. | Aoki Y | Nature genetics | 2005 | PMID: 16170316 |
| click to load more citations click to collapse | ||||
Conditions - Somatic
| Tumor type
Help
The tumor type for this variant-condition (RCV) record in ClinVar. |
Clinical impact (# of submissions)
Help
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
Help
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
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
Variation/condition record
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
|---|---|---|---|---|
|
Tier I (Strong)
- diagnostic
- supports diagnosis
(1)
|
Aug 2, 2023 | RCV006253539.1 |
Submissions - Somatic
|
Clinical impact
Help
The submitted somatic clinical impact 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) |
Tumor type
Help
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
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
Help
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. |
|---|
|
Tier I (Strong)
- Diagnostic
-
supports diagnosis (Aug 02, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Embryonal rhabdomyosarcoma |
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV007105287.1
First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025 |
Comment:
show
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in embryonal rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 6092966, 24224811). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 34166060, 24436047, 2680062, 19681119, 24332040, 25768946). (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
|
|
Comment:
The Gly12Cys variant in HRAS has been reported in the literature in six individu als with severe neonatal Costello syndrome (Kerr 2006, Lo 2008, Lin 2009, Niihor i 2011, Lorenz 2012). This variant has been reported to have occurred de novo in one proband (Lorenz 2012). Several other DNA variants affecting codon 12 of HRA S are commonly observed in patients with Costello syndrome (Niihori 2011). There fore, this variant is highly likely to be pathogenic.
Comment:
Variant summary: HRAS c.34G>T (p.Gly12Cys) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250294 control chromosomes (gnomAD). c.34G>T has been reported in the literature in multiple individuals affected with Costello Syndrome (e.g. Niihori_2011, McCormick_2013, Choi_2019). These data indicate that the variant is very likely to be associated with disease. In functional studies, Niihori et al (Niihori_2011) report that there was an increase in guanosine triphosphate (GTP)-bound HRAS and activation of RAS signaling pathway (as measured by the activation of ELK1 and c-Jun) in cells transfected with the variant of interest. In addition, HGMD database reports several other missense variants affecting the same codon and nearby codons (e.g. p.G12R, p.G12S, p.G12V, p.G12A, p.G13D, p.G13C) suggesting this area might be a mutational hotspot. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The variant in c.34G>T (p.Gly12Cys) in HRAS gene is reported as pathogenic for Costello syndrome and other HRAS-related diseases in ClinVar (Variation ID: 12613) and in the Global Variome shared LOVD database v.3.0 (genomic variant: #0000345686). There is no information on frequency in gnomAD or 1000 Genomes Project. The variant has been reported in in multiple individuals affected with Costello Syndrome (Choi et al., 2019, PMID: 31394527; McCormick et al., 2013, PMID: 23429430; Niihori et al., 2011, PMID: 21850009).
Comment:
Published functional studies of the G12C variant have shown that it results in increased active, GTP-bound HRAS (Niihori et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 16443854, 24224811, 23093928, 24803665, 31394527, 22926243, 21850009, 16155195, 18039947, 33258288, 29493581)
Comment:
The HRAS c.34G>T; p.Gly12Cys variant (rs104894229; ClinVar Variation ID: 12613) is reported in the literature as a recurrent de novo variant in multiple individuals affected with Costello syndrome (Choi 2019, Kerr 2006, Lorenz 2012). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine residues at codons 12 and 13 are frequently altered in both Costello syndrome patients (Aoki 2005, Estep 2006, Gripp 2005, Kerr 2006, Niihori 2011). Functional characterization of the p.Gly12Cys protein indicates increased downstream MEK signaling activity (Niihori 2011), consistent with the established disease mechanism of Costello syndrome. Based on available information, this variant is considered to be pathogenic. References: Choi N et al. Phenotypic and Genetic Characteristics of Five Korean Patients with Costello Syndrome. Cytogenet Genome Res. 2019;158(4):184-191. PMID: 31394527. Kerr B et al. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J Med Genet. 2006 May;43(5):401-5. PMID: 16443854 Lorenz S et al Two cases with severe lethal course of Costello syndrome associated with HRAS p.G12C and p.G12D. Eur J Med Genet. 2012 Nov;55(11):615-9. PMID: 22926243. Niihori T et al. HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome. J Hum Genet. 2011 Oct;56(10):707-15. PMID: 21850009.
Comment:
ACMG Criteria:PP3, PP5, PM2_P, PM1, PM5, PS3; Variant was found in heterozygous state
Comment:
Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.;De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.;Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc).;Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 12 of the HRAS protein (p.Gly12Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Costello syndrome (PMID: 16443854, 18039947, 22926243). ClinVar contains an entry for this variant (Variation ID: 12613). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HRAS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HRAS function (PMID: 21850009). This variant disrupts the p.Gly12 amino acid residue in HRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16170316, 16372351, 16443854, 16835863, 17601930, 18042262, 21850009, 22420426, 28027064). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in embryonal rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 6092966, 24224811). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 34166060, 24436047, 2680062, 19681119, 24332040, 25768946).
Comment:
The NM_176795.5 c.34G>T is a missense variant in HRAS gene.Not observed at significant frequency in large population cohorts (gnomAD). This variant has been reported in the literature in multiple individuals affected with Costello Syndrome (PMID 31394527, 22926243, 24637993, 21850009). The c.34G>T variant in the HRAS gene of the tested sample was confirmed to be a de novo variant through parental sample verification. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.788). At the same base site, it leads to another amino acid variant c.34G>A (p.Gly12Ser), which has been confirmed to be pathogenic. This variant has been reported in ClinVar as pathogenic (Accession: VCV000012613.62). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
Variant classified using ACMG guidelines
Citations for somatic classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genomic Classification and Clinical Outcome in Rhabdomyosarcoma: A Report From an International Consortium. | Shern JF | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2021 | PMID: 34166060 |
| Clonality and evolutionary history of rhabdomyosarcoma. | Chen L | PLoS genetics | 2015 | PMID: 25768946 |
| Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. | Shern JF | Cancer discovery | 2014 | PMID: 24436047 |
| Targeting oxidative stress in embryonal rhabdomyosarcoma. | Chen X | Cancer cell | 2013 | PMID: 24332040 |
| Kinetic mechanisms of mutation-dependent Harvey Ras activation and their relevance for the development of Costello syndrome. | Wey M | Biochemistry | 2013 | PMID: 24224811 |
| RAS signaling dysregulation in human embryonal Rhabdomyosarcoma. | Martinelli S | Genes, chromosomes & cancer | 2009 | PMID: 19681119 |
| Detection of point mutations in N-ras and K-ras genes of human embryonal rhabdomyosarcomas using oligonucleotide probes and the polymerase chain reaction. | Stratton MR | Cancer research | 1989 | PMID: 2680062 |
| Biological properties of human c-Ha-ras1 genes mutated at codon 12. | Seeburg PH | Nature | 1984 | PMID: 6092966 |
Text-mined citations for rs104894229 ...
HelpThese 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 Jul 06, 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.