Submissions for variant NM_005343.4(HRAS):c.37G>C (p.Gly13Arg)

dbSNP: rs104894228

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Medicine Lab, University of California San Francisco	RCV001376004	SCV001573009	pathogenic	Non-immune hydrops fetalis	2019-05-29	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001781319	SCV002016631	likely pathogenic	Costello syndrome	2019-12-18	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813211	SCV002060964	pathogenic	Noonan syndrome and Noonan-related syndrome	2021-05-08	criteria provided, single submitter	clinical testing
Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam	RCV001781319	SCV003934962	pathogenic	Costello syndrome	2022-06-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001781319	SCV004039160	pathogenic	Costello syndrome	2023-08-14	criteria provided, single submitter	clinical testing	Variant summary: HRAS c.37G>C (p.Gly13Arg) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250330 control chromosomes (gnomAD). c.37G>C has been reported in numerous publications as a somatic mutation found in various types of cancers and at least one de novo case who may have Costello Syndrome (Sparks_2020). These data indicate that the variant is likely to be associated with disease. At least three publications report experimental evidence evaluating an impact on protein function and functional analysis of HRAS c.37G>C confirmed constitutive activation of the MAPK and PI3KK-Akt signaling pathways (Spoerner_2010, Groesser_2012, Lopes-Ventura_2018). In addition, Glycine 13 is one of the two most mutated amino acids in Costello Syndrome, and several other variants located at codon 13 have been associated with Costello Syndrome (G13D, G13V, G13C; PMID: 24224811) in HGMD and classified as DV in our lab. The following publications have been ascertained in the context of this evaluation (PMID: 20937837, 22683711, 30191474, 33027564). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV003458340	SCV004176935	pathogenic	Epidermolytic nevus	2023-10-16	criteria provided, single submitter	clinical testing	The HRAS c.37G>C (p.Gly13Arg) variant was identified at an allelic fraction likely supporting somatic origin. This variant has been reported in multiple individuals with epidermal nevus and nevus spilus (Farschtschi S et al., PMID: 25928347; Lim YH et al., PMID: 24006476; Hafner C et al., PMID: 22499344; Bender RP et al., PMID: 23599145; Sarin KY et al., PMID: 24390138; Sarin KY et al., PMID: 23884457). This variant has been reported in the ClinVar database as a pathogenic/likely pathogenic variant by multiple submitters (ClinVar ID: 35554) and in multiple cancer cases as a somatic variant in the cancer database COSMIC (Cosmic ID: COSV54236651). This variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. The HRAS c.37G>C (p.Gly13Arg) variant resides within a GTP binding domain of HRAS that is defined as a critical functional domain (Wey M et al., PMID: 24224811). Computational predictors indicate that the variant is damaging, evidence that correlates with impact on HRAS function and in support of this prediction, functional studies show that this variant results in activation of the Ras-Raf-MAPK and PI3K-Akt signaling pathways and increased cellular proliferation (Groesser L et al., PMID: 22683711). The HRAS gene is defined by ClinGen's RASopathy expert panel as a gene with a low rate of benign missense variation and where pathogenic missense variants are a common disease mechanism (Gelb BD et al., PMID: 29493581). Based on the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the HRAS c.37G>C (p.Gly13Arg) variant is classified as pathogenic.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000032852	SCV005902203	pathogenic	Epidermal nevus	2024-11-14	criteria provided, single submitter	clinical testing	An HRAS c.37G>C (p.Gly13Arg) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals with epidermal nevus (Groesser L et al., PMID: 22683711; Hafner C et al., PMID: 22499344; Kitamura S et al., PMID: 28247919; Zuntini R et al., PMID: 37636262). This variant has been reported in the ClinVar database as a pathogenic/likely pathogenic variant by multiple submitters, including our laboratory (ClinVar ID: 35554) and in multiple cancer cases in the cancer database COSMIC (Cosmic ID: COSV54236651). This variant is absent from the general population (gnomAD v.4.1.0), indicating it is not a common variant. The HRAS c.37G>C (p.Gly13Arg) variant resides within a GTP binding domain of HRAS that is defined as a critical functional domain (Wey M et al., PMID: 24224811). Computational predictors indicate that the variant is damaging, evidence that correlates with impact on HRAS function and in support of this prediction, functional studies show that this variant results in activation of the Ras-Raf-MAPK and PI3K-Akt signaling pathways with increased cellular proliferation (Groesser L et al., PMID: 22683711). The HRAS gene is defined by ClinGen's RASopathy expert panel as a gene with a low rate of benign missense variation and where pathogenic missense variants are a common disease mechanism (Gelb BD et al., PMID: 29493581). Based on available information and an internally developed protocol informed by the ACMG/AMP guidelines for variant interpretation and gene-specific practices from the ClinGen Criteria Specification Registry (Leon-Quintero FZ et al., PMID: 39434542), the HRAS c.37G>C (p.Gly13Arg) variant is classified as pathogenic.
OMIM	RCV000029212	SCV000051858	pathogenic	Nevus sebaceous	2014-06-01	no assertion criteria provided	literature only
OMIM	RCV000029213	SCV000051859	pathogenic	Linear nevus sebaceous syndrome	2014-06-01	no assertion criteria provided	literature only
OMIM	RCV000032852	SCV000056621	pathogenic	Epidermal nevus	2014-06-01	no assertion criteria provided	literature only
OMIM	RCV000173005	SCV000224024	pathogenic	NEVUS SPILUS, SOMATIC	2014-06-01	no assertion criteria provided	literature only
OMIM	RCV000173006	SCV000224025	pathogenic	SPITZ NEVUS, SOMATIC	2014-06-01	no assertion criteria provided	literature only
Yale Center for Mendelian Genomics, Yale University	RCV000029212	SCV000611560	pathogenic	Nevus sebaceous	2012-10-25	no assertion criteria provided	literature only
Institute of Medical Sciences, Banaras Hindu University	RCV001255682	SCV001432247	pathogenic	Lip and oral cavity carcinoma	2019-04-30	no assertion criteria provided	research
Yale Center for Mendelian Genomics, Yale University	RCV001849283	SCV002106447	likely pathogenic	cutaneous-skeletal hypophosphatemia syndrome	2016-08-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004739310	SCV005367484	pathogenic	HRAS-related disorder	2024-03-18	no assertion criteria provided	clinical testing	The HRAS c.37G>C variant is predicted to result in the amino acid substitution p.Gly13Arg. This variant has been reported to occur de novo in a patient with non-immune hydrops fetalis and suspected Costello syndrome (Sparks et al 2020. PubMed ID: 33027564). Several other amino substitutions at this position (p.Gly13Ser, p.Gly13Asp, p.Gly13Cys, p.Gly13Val) have also been reported in patients with non-immune hydrops fetalis, Costello syndrome, or multiple congenital anomalies (Sparks et al 2020. PubMed ID: 33027564; Lefebvre. 2021. PubMed ID: 32732226; Estep. 2006. PubMed ID: 16372351). This variant has been reported as a postzygotic somatic change in skin lesions from individuals with nevus sebaceous and in an individual with Schimmelpenning syndrome (Groesser at al. 2012. PubMed ID: 22683711). It has also been reported as a recurrent somatic change in sporadic medullary thyroid carcinomas (Ciampi et al. 2019. PubMed ID: 31605946), and keratinocytic epidermal nevi (Hafner et al. 2012. PubMed ID: 22499344). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted in ClinVar as pathogenic by many outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/35554/). This variant is interpreted as pathogenic.