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

dbSNP: rs104894228

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000678903	SCV000616363	pathogenic	Noonan syndrome	2017-04-03	reviewed by expert panel	curation	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000013440	SCV000062140	pathogenic	Costello syndrome	2010-06-29	criteria provided, single submitter	clinical testing	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).
GeneDx	RCV000207504	SCV000207847	pathogenic	not provided	2022-06-21	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000013440	SCV000259986	pathogenic	Costello syndrome	2024-02-22	criteria provided, single submitter	clinical testing	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). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) 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.
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000207504	SCV000263057	pathogenic	not provided	2014-06-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000013440	SCV000807270	pathogenic	Costello syndrome	2024-01-09	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000762847	SCV000893207	pathogenic	Large congenital melanocytic nevus; Linear nevus sebaceous syndrome; Malignant tumor of urinary bladder; Costello syndrome; Epidermal nevus; Thyroid cancer, nonmedullary, 2	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000149831	SCV000917529	pathogenic	RASopathy	2018-09-24	criteria provided, single submitter	clinical testing	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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813188	SCV002060965	pathogenic	Noonan syndrome and Noonan-related syndrome	2018-06-01	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV000013440	SCV003924421	likely pathogenic	Costello syndrome		criteria provided, single submitter	clinical testing	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.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000013440	SCV004809475	pathogenic	Costello syndrome	2024-04-04	criteria provided, single submitter	clinical testing
Daryl Scott Lab, Baylor College of Medicine	RCV003421918	SCV005871028	pathogenic	HRAS-related disorder	2024-01-01	criteria provided, single submitter	clinical testing	PM1, PM2, PS2_VeryStrong, PS4_Moderate, PM1, PM2, PP2, PP3,
OMIM	RCV000013440	SCV000033687	pathogenic	Costello syndrome	2011-04-01	no assertion criteria provided	literature only
Baylor Genetics	RCV000149831	SCV000196675	pathogenic	RASopathy		no assertion criteria provided	clinical testing	Variant classified using ACMG guidelines
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678903	SCV000805106	pathogenic	Noonan syndrome	2017-08-24	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000207504	SCV001799200	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000207504	SCV001955013	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003421918	SCV004117466	pathogenic	HRAS-related disorder	2024-05-06	no assertion criteria provided	clinical testing	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.
Solve-RD Consortium	RCV004767004	SCV005091323	likely pathogenic	Linear nevus sebaceous syndrome	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team