VCV000012606.43 - ClinVar

NM_005343.4(HRAS):c.37G>T (p.Gly13Cys)

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Pathogenic

for Noonan syndrome

Classification is based on the expert panel submission

Apr 2017 by ClinGen RASopathy Variant Curation Expert Panel

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

Clinical impact

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Tier I (Strong) for Rhabdomyosarcoma

This classification is based on the single submission received

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.

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005343.4(HRAS):c.37G>T (p.Gly13Cys)

Variation ID: 12606 Accession: VCV000012606.43

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.5 11: 534286 (GRCh38) [ NCBI UCSC ] 11: 534286 (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 1, 2014	Jun 20, 2026	Apr 3, 2017
Somatic - Clinical impact	Nov 22, 2025	Nov 22, 2025	Oct 22, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_005343.4:c.37G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005334.1:p.Gly13Cys	missense
NM_176795.5:c.37G>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_789765.1:p.Gly13Cys	missense
NM_001130442.3:c.37G>T	NP_001123914.1:p.Gly13Cys	missense
NM_001318054.2:c.-283G>T		5 prime UTR
NM_005343.2:c.37G>A
NC_000011.10:g.534286C>A
NC_000011.9:g.534286C>A
NG_007666.1:g.6265G>T
LRG_506:g.6265G>T
LRG_506t1:c.37G>T	LRG_506p1:p.Gly13Cys
	P01112:p.Gly13Cys

... more HGVS ... less HGVS

Protein change

G13C

Other names

p.G13C:GGT>TGT
NM_005343.3(HRAS):c.37G>T

Canonical SPDI

NC_000011.10:534285:C:A

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: CA295247 UniProtKB: P01112#VAR_026107 OMIM: 190020.0007 dbSNP: rs104894228 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.
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.
Costello syndrome	Pathogenic/Likely pathogenic (8)	criteria provided, multiple submitters, no conflicts	Apr 30, 2026	RCV000013440.52
RASopathy	Pathogenic (2)	criteria provided, single submitter	Sep 24, 2018	RCV000149831.4
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jul 1, 2025	RCV000207504.17
Noonan syndrome	Pathogenic (2)	reviewed by expert panel	Apr 3, 2017	RCV000678903.4
Costello syndrome Epidermal nevus Large congenital melanocytic nevus Linear nevus sebaceous syndrome Malignant tumor of urinary bladder Thyroid cancer, nonmedullary, 2	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000762847.3
Noonan syndrome and Noonan-related syndrome	Pathogenic (1)	criteria provided, single submitter	Jun 1, 2018	RCV001813188.4
HRAS-related disorder	Pathogenic (2)	criteria provided, single submitter	Jan 1, 2024	RCV003421918.6
Linear nevus sebaceous syndrome	Likely pathogenic (1)	no assertion criteria provided	Jun 1, 2022	RCV004767004.2

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.
Pathogenic (Apr 03, 2017) C Contributing to aggregate classification	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1)	Noonan syndrome (Autosomal dominant inheritance)	ClinGen RASopathy Variant Curation Expert Panel FDA Recognized Database Accession: SCV000616363.4 First in ClinVar: Dec 19, 2017 Last updated: Dec 11, 2022	Publications: PubMed (3) PubMed: 16329078‚ 21438134‚ 29493581 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/77fd6395-3146-46f0-86ca-08fb626eb660 Comment: show The c.37G>T (p.Gly13Cys) variant in HRAS has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 21438134, 16329078). The p.Gly13Cys variant has been identified in at least 3 other independent occurrence in patients with clinical features of a RASopathy (PS4_Moderate; PMID: 16372351). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the HRAS 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.Gly13Cys 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 HRAS (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 (PMID: 29493581): PP2, PP3, PM1, PM2, PS4_Moderate, PS2_VeryStrong. (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Pathogenic (Oct 31, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	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: SCV000893207.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30 pmc: 4544753 pmc: 4544753 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 (Jun 29, 2010) N Not contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	Costello syndrome (Autosomal dominant inheritance)	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000062140.5 First in ClinVar: May 03, 2013 Last updated: Dec 19, 2017	Publications: PubMed (3) PubMed: 16329078‚ 16372351‚ 17211612 Comment: show The Gly13Cys variant has previously been associated with the clinical features o f Costello syndrome (Estep 2006, Gripp 2006, Kratz 2007). This variant has been shown to have occurred de novo in at least one individual. In summary, this vari ant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org /LMM). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Number of individuals with the variant: 5

Pathogenic (Jan 01, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	HRAS-related disorder	Daryl Scott Lab, Baylor College of Medicine Accession: SCV005871028.1 First in ClinVar: Mar 04, 2025 Last updated: Mar 04, 2025	Comment: show PM1, PM2, PS2_VeryStrong, PS4_Moderate, PM1, PM2, PP2, PP3, (less) Observation: 1 Collection method: clinical testing Allele origin: de novo Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: de novo Affected status: yes Zygosity: 1 Single Heterozygote

Pathogenic (Oct 08, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (Variantyx Assertion Criteria 2022)	Costello syndrome (Autosomal dominant inheritance)	Variantyx, Inc. Accession: SCV007593549.1 First in ClinVar: May 16, 2026 Last updated: May 16, 2026	Publications: PubMed (3) PubMed: 16372351‚ 21438134‚ 21850009 Comment: show This is a nonsynonymous variant in the HRAS gene (OMIM: 190020). Pathogenic variants in this gene have been associated with autosomal dominant Costello syndrome. This variant likely occurred de novo in the current proband, and individuals reported in the published literature; however, the possibility of parental germline mosaicism cannot be excluded (PMID: 21438134, 16372351) (PS2_Very_Strong). Functional studies have shown that this variant alters HRAS protein function (PMID: 21850009) (PS3) and multiple computational algorithms predict a deleterious effect for this variant (REVEL score: 0.745) (PP3). This variant lies within a known hotspot for pathogenic variants or a well-established critical functional domain of the HRAS protein (PM1). It is absent from control populations (https://gnomad.broadinstitute.org/) (PM2). Other reputable laboratories have reported this variant as pathogenic or likely pathogenic, and this classification has been validated by an expert panel in ClinVar. This variant is classified as pathogenic for autosomal dominant Costello syndrome. (less) 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 (Sep 24, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Rasopathy	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000917529.1 First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019	Publications: PubMed (2) PubMed: 21438134‚ 23429430 Comment: show Variant summary: HRAS c.37G>T (p.Gly13Cys) results in a non-conservative amino acid change located in the Small GTP-binding protein domain 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 276492 control chromosomes (gnomAD). c.37G>T has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions and occurs at a codon that is known to be associated with disease (McCormick_2013, Gripp_2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic/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 (Jun 21, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000207847.13 First in ClinVar: Feb 20, 2016 Last updated: Mar 04, 2023	Comment: show Functional studies demonstrate that G13C alters GTP and GDP dissociation rates resulting in increased active GTP-bound HRAS, which upregulates the Ras/MAPK pathway (Wey et al., 2013); The majority of missense variants in this gene are considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23093928, 16372351, 24803665, 24224811, 16329078, 21438134, 19213030, 28337834, 28973083, 28371260, 16835863, 33240318, 33482860, 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 04, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Costello syndrome	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre Accession: SCV004809475.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 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

Pathogenic (Jan 09, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Costello syndrome	Baylor Genetics Accession: SCV000807270.3 First in ClinVar: Dec 19, 2017 Last updated: Jun 09, 2024	Publications: PubMed (1) PubMed: 25326635 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 (Jun 04, 2014) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	none provided	Molecular Diagnostics Lab, Nemours Children's Health, Delaware Accession: SCV000263057.2 First in ClinVar: Feb 20, 2016 Last updated: Apr 13, 2025	Publications: PubMed (5) PubMed: 16329078‚ 16372351‚ 168335863‚ 19213030‚ 21438134 Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Number of individuals with the variant: 1 Age: 10-19 years Sex: female

Pathogenic (Apr 30, 2026) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Costello syndrome	Institute of Human Genetics, Heidelberg University Accession: SCV007606622.1 First in ClinVar: Jun 20, 2026 Last updated: Jun 20, 2026	Comment: show PM2_supp, PS4_mod, PM1, PS2_str, PP3_supp (less) Observation: 1 Collection method: clinical testing Allele origin: de novo Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: de novo Affected status: yes Number of individuals with the variant: 1 Sex: male

Pathogenic (Jul 01, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV006330607.6 First in ClinVar: Sep 22, 2025 Last updated: Jun 20, 2026	Comment: show HRAS: PS4, PM1, PM2, PM5, PS2:Moderate, PP2 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1

Pathogenic (Jun 01, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Noonan syndrome and Noonan-related syndrome	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002060965.1 First in ClinVar: Jan 20, 2022 Last updated: Jan 20, 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

Likely pathogenic (-) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Costello syndrome (Autosomal dominant inheritance)	Lifecell International Pvt. Ltd Accession: SCV003924421.1 First in ClinVar: May 20, 2023 Last updated: May 20, 2023	Publications: PubMed (1) PubMed: 23429430 Comment: show A Heterozygous Missense variant c.37G>T in Exon 2 of the HRAS gene that results in the amino acid substitution p.Gly13Cys was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variation ID:12606]. The observed variation has been previously reported in patients affected with Costello syndrome (McCormick, Elizabeth M et al., 2013). For these reasons, this variant has been classified as Likely Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Zygosity: 1 Single Heterozygote Ethnicity/Population group: Asian Geographic origin: India Platform type: Next-generation exome sequencing Platform name: NovaSeq 6000

Pathogenic (Aug 18, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Costello syndrome	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000259986.8 First in ClinVar: Jan 31, 2016 Last updated: Feb 15, 2026	Publications: PubMed (5) PubMed: 16329078‚ 16372351‚ 18042262‚ 21438134‚ 21850009 Comment: show This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 13 of the HRAS protein (p.Gly13Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Costello syndrome (PMID: 16329078, 16372351, 18042262, 21438134). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12606). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt HRAS function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HRAS function (PMID: 21850009). This missense change is located in codon 13 of the HRAS gene product. Genetic studies of individuals with Costello syndrome show that more than 90% of all HRAS missense variants in these patients occur in either codon 12 or 13 of this gene (PMID: 16329078, 18042262, 21438134, 16372351). This indicates that missense changes involving these two codons are a common cause of disease. 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 06, 2024) N Not contributing to aggregate classification	no assertion criteria provided	HRAS-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV004117466.2 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: show The HRAS c.37G>T variant is predicted to result in the amino acid substitution p.Gly13Cys. This variant was reported in multiple individuals with Costello syndrome and in at least two individuals it was documented as de novo (see for example - Estep et al. 2006. PubMed ID: 16372351; Table e3, Meng et al. 2017. PubMed ID: 28973083; Table S1, Zhu et al. 2020. PubMed ID: 33240318). Functional studies found this variant impacts HRAS function (Cheng et al. 2012. PubMed ID: 23093928 ). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been interpreted as pathogenic by ClinGen's RASopathy variant curation expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/12606/). Additionally, alternate missense variants (p.Gly13Arg, p.Gly13Asp, p.Gly13Val) have been reported as pathogenic (Sparks et al. 2020. PubMed ID: 33027564; Lefebvre et al. 2021. PubMed ID: 32732226). 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

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	Rasopathy	Baylor Genetics Accession: SCV000196675.1 First in ClinVar: Jan 16, 2015 Last updated: Jan 16, 2015	Publications: PubMed (2) PubMed: 21438134‚ 21495179 Comment: show Variant classified using ACMG guidelines (less) 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 01, 2011) N Not contributing to aggregate classification	no assertion criteria provided	COSTELLO SYNDROME	OMIM Accession: SCV000033687.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 25, 2025	Publications: PubMed (3) PubMed: 16835863‚ 19213030‚ 21438134 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: Sol-Church et al. (2006) found that of 42 patients with Costello syndrome (218040) and heterozygous de novo missense mutations involving either glycine-12 or -13 of … (more) Sol-Church et al. (2006) found that of 42 patients with Costello syndrome (218040) and heterozygous de novo missense mutations involving either glycine-12 or -13 of the HRAS gene, only 1 carried a gly13-to-cys (G13C) substitution (c.37G-A, NM_005343.2). Piccione et al. (2009) reported a premature male infant born at 29 weeks' gestation due to fetal distress who was found to have Costello syndrome due to the G13C mutation. The characteristic facial features were not apparent until about 4 months of age, when he was noted to have relative macrocephaly, coarse face with hypertelorism, downslanting palpebral fissures, epicanthal folds, prominent eyes, short nose, low-set ears, large mouth, short neck, loose skin of hands and feet, sparse hair, hyperpigmented skin, deep palmar creases, joint laxity, reduced subcutaneous adipose tissue, and bilateral cryptorchidism. At 11 months of age, he had delayed motor development with central hypotonia, but adequate mental and speech development. Papillomata were not present. Piccione et al. (2009) noted that the distinctive features of Costello syndrome may be absent during the first months of life, especially in preterm infants who often have failure to thrive and decreased subcutaneous adipose tissue. The striking facial features of the disorder become more evident after the critical neonatal period. Gripp et al. (2011) examined 12 individuals with Costello syndrome due to the G13C mutation and compared the phenotype to those with the G12S (190020.0003) mutation. Individuals with G13C had many typical findings including polyhydramnios, failure to thrive, hypertrophic cardiomyopathy, macrocephaly, posterior fossa crowding, and developmental delay. Their facial features were less coarse and short stature was less severe. Statistically significant differences included the absence of several common features, including multifocal atrial tachycardia, ulnar deviation of the wrist, and papillomata; a noteworthy absence of malignant tumors did not reach statistical significance. There were some novel ectodermal findings associated with the G13C mutation, including loose anagen hair and long eyelashes requiring trimming (termed 'dolichocilia'). (less)

Pathogenic (Aug 24, 2017) N Not contributing to aggregate classification	no assertion criteria provided	Noonan syndrome	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital Accession: SCV000805106.1 First in ClinVar: Sep 17, 2018 Last updated: Sep 17, 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

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001799200.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 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 (-) 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: SCV001955013.1 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

Likely pathogenic (Jun 01, 2022) N Not contributing to aggregate classification	no assertion criteria provided	Linear nevus sebaceous syndrome	Solve-RD Consortium Accession: SCV005091323.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 Comment: Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more) Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)	Publications: PubMed (1) PubMed: 39825153 Comment: show Variant confirmed as disease-causing by referring clinical team (less) Observation: 1 Collection method: provider interpretation Allele origin: inherited Affected status: yes Observation 1 Collection method: provider interpretation Allele origin: inherited Affected status: yes

Comment:

The c.37G>T (p.Gly13Cys) variant in HRAS has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 21438134, 16329078). The p.Gly13Cys variant has been identified in at least 3 other independent occurrence in patients with clinical features of a RASopathy (PS4_Moderate; PMID: 16372351). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the HRAS 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.Gly13Cys 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 HRAS (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 (PMID: 29493581): PP2, PP3, PM1, PM2, PS4_Moderate, PS2_VeryStrong.

Comment:

The Gly13Cys variant has previously been associated with the clinical features o f Costello syndrome (Estep 2006, Gripp 2006, Kratz 2007). This variant has been shown to have occurred de novo in at least one individual. In summary, this vari ant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org /LMM).

Comment:

This is a nonsynonymous variant in the HRAS gene (OMIM: 190020). Pathogenic variants in this gene have been associated with autosomal dominant Costello syndrome. This variant likely occurred de novo in the current proband, and individuals reported in the published literature; however, the possibility of parental germline mosaicism cannot be excluded (PMID: 21438134, 16372351) (PS2_Very_Strong). Functional studies have shown that this variant alters HRAS protein function (PMID: 21850009) (PS3) and multiple computational algorithms predict a deleterious effect for this variant (REVEL score: 0.745) (PP3). This variant lies within a known hotspot for pathogenic variants or a well-established critical functional domain of the HRAS protein (PM1). It is absent from control populations (https://gnomad.broadinstitute.org/) (PM2). Other reputable laboratories have reported this variant as pathogenic or likely pathogenic, and this classification has been validated by an expert panel in ClinVar. This variant is classified as pathogenic for autosomal dominant Costello syndrome.

Comment:

Variant summary: HRAS c.37G>T (p.Gly13Cys) results in a non-conservative amino acid change located in the Small GTP-binding protein domain 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 276492 control chromosomes (gnomAD). c.37G>T has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions and occurs at a codon that is known to be associated with disease (McCormick_2013, Gripp_2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

Functional studies demonstrate that G13C alters GTP and GDP dissociation rates resulting in increased active GTP-bound HRAS, which upregulates the Ras/MAPK pathway (Wey et al., 2013); The majority of missense variants in this gene are considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23093928, 16372351, 24803665, 24224811, 16329078, 21438134, 19213030, 28337834, 28973083, 28371260, 16835863, 33240318, 33482860, 29493581)

Comment:

A Heterozygous Missense variant c.37G>T in Exon 2 of the HRAS gene that results in the amino acid substitution p.Gly13Cys was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variation ID:12606]. The observed variation has been previously reported in patients affected with Costello syndrome (McCormick, Elizabeth M et al., 2013). For these reasons, this variant has been classified as Likely Pathogenic.

Comment:

Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in 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 (PMID: 25705018). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 26349418, 24436047).

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 13 of the HRAS protein (p.Gly13Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Costello syndrome (PMID: 16329078, 16372351, 18042262, 21438134). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12606). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt HRAS function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HRAS function (PMID: 21850009). This missense change is located in codon 13 of the HRAS gene product. Genetic studies of individuals with Costello syndrome show that more than 90% of all HRAS missense variants in these patients occur in either codon 12 or 13 of this gene (PMID: 16329078, 18042262, 21438134, 16372351). This indicates that missense changes involving these two codons are a common cause of disease. For these reasons, this variant has been classified as Pathogenic.

Comment:

The HRAS c.37G>T variant is predicted to result in the amino acid substitution p.Gly13Cys. This variant was reported in multiple individuals with Costello syndrome and in at least two individuals it was documented as de novo (see for example - Estep et al. 2006. PubMed ID: 16372351; Table e3, Meng et al. 2017. PubMed ID: 28973083; Table S1, Zhu et al. 2020. PubMed ID: 33240318). Functional studies found this variant impacts HRAS function (Cheng et al. 2012. PubMed ID: 23093928 ). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been interpreted as pathogenic by ClinGen's RASopathy variant curation expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/12606/). Additionally, alternate missense variants (p.Gly13Arg, p.Gly13Asp, p.Gly13Val) have been reported as pathogenic (Sparks et al. 2020. PubMed ID: 33027564; Lefebvre et al. 2021. PubMed ID: 32732226). This variant is interpreted as pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genomic reanalysis of a pan-European rare-disease resource yields new diagnoses.	Laurie S	Nature medicine	2025	PMID: 39825153
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
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
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
Neurocognitive, adaptive, and behavioral functioning of individuals with Costello syndrome: a review.	Axelrad ME	American journal of medical genetics. Part C, Seminars in medical genetics	2011	PMID: 21495179
Phenotypic analysis of individuals with Costello syndrome due to HRAS p.G13C.	Gripp KW	American journal of medical genetics. Part A	2011	PMID: 21438134
A premature infant with Costello syndrome due to a rare G13C HRAS mutation.	Piccione M	American journal of medical genetics. Part A	2009	PMID: 19213030
Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome.	Schulz AL	Clinical genetics	2008	PMID: 18042262
An unexpected new role of mutant Ras: perturbation of human embryonic development.	Kratz CP	Journal of molecular medicine (Berlin, Germany)	2007	PMID: 17211612
Paternal bias in parental origin of HRAS mutations in Costello syndrome.	Sol-Church K	Human mutation	2006	PMID: 16835863
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
HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation.	Gripp KW	American journal of medical genetics. Part A	2006	PMID: 16329078
-	-	-	-	PMID: 168335863
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/77fd6395-3146-46f0-86ca-08fb626eb660	-	-	-	-
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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.
Rhabdomyosarcoma	Tier I (Strong) - diagnostic - supports diagnosis (1)		Oct 22, 2022	RCV006253538.1

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 (Oct 22, 2022) C Contributing to aggregate classification	criteria provided, single submitter (AMP/ASCO/CAP Guidelines, 2017)	Rhabdomyosarcoma	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV007105286.1 First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025	Publications: PubMed (3) PubMed: 24436047‚ 25705018‚ 26349418 Comment: show Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in 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 (PMID: 25705018). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 26349418, 24436047). (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:

Citations for somatic classification of this variant

Title	Author	Journal	Year	Link
Pediatric Rhabdomyosarcoma.	Shern JF	Critical reviews in oncogenesis	2015	PMID: 26349418
Comparative analysis of KRAS codon 12, 13, 18, 61, and 117 mutations using human MCF10A isogenic cell lines.	Stolze B	Scientific reports	2015	PMID: 25705018
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

Text-mined citations for rs104894228 ...

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 Jul 06, 2026