Submissions for variant NM_005343.4(HRAS):c.35G>A (p.Gly12Asp)

dbSNP: rs104894230

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038460	SCV000062136	pathogenic	Costello syndrome	2011-03-09	criteria provided, single submitter	clinical testing	The Gly12Asp variant in HRAS has been reported in the literature in four individ uals with severe neonatal Costello syndrome (Lo 2008, Kuniba 2009, Sinico 2010). This variant has been reported to have occurred de novo in two probands (Lo 200 8, Sinico 2010). This variant has been observed as a somatic change in tumor tis sue. Several other variants in codon 12 of HRAS are commonly observed in Costell o syndrome patients (Lin 2011). Therefore, it is highly likely that this variant is pathogenic.
GeneDx	RCV000212496	SCV000207844	pathogenic	not provided	2018-07-04	criteria provided, single submitter	clinical testing	The G12D variant in the HRAS gene has been reported previously as de novo and in association with Costello syndrome (Lo et al., 2008; Lorenz et al., 2012). Functional studies show G12D results in increased levels of the active, GTP-bound HRAS protein (Niihori et al., 2011). This variant is not observed in large population cohorts (Lek et al., 2016). The G12D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Multiple pathogenic missense variants at this residue (G12S, G12C, G12V, G12A) have been reported in association with Costello syndrome (Aoki et al., 2005; Kerr et al., 2006).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000149830	SCV000919525	pathogenic	RASopathy	2017-10-30	criteria provided, single submitter	clinical testing	Variant summary: The HRAS c.35G>A (p.Gly12Asp) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 276492 control chromosomes. It has been reported in many CS cases and most of them with severe clinical presentations. Functional assays showed the variant to have increased activity (Niihori_2011). Variants involving codon 12 (such as p.G12S, p.G12A, p.G12C, p.G12D) have been reported in numerous affected individuals indicating it is mutation hotspot. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae	RCV000038460	SCV001204990	pathogenic	Costello syndrome	2019-06-09	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with aspartic acid at codon 12 of the HRAS protein (p.Gly12Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in many individuals affected with Costello syndrome (PMID: 26916728, 18642361, 21850009, 27102959, 18039947, 22926243). In several individuals the variant was found to be de novo. ClinVar contains an entry for this variant (Variation ID: 12612). This variant has been reported to affect HRAS protein function (PMID: 24224811, 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, 20979192, 21834037, 21850009, 22317973, 23751039). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000212496	SCV001247462	pathogenic	not provided	2019-05-01	criteria provided, single submitter	clinical testing
Genomic Medicine Lab, University of California San Francisco	RCV001375956	SCV001572945	pathogenic	Non-immune hydrops fetalis	2020-04-30	criteria provided, single submitter	clinical testing
3billion	RCV000038460	SCV002011965	pathogenic	Costello syndrome	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic (SCV000207860, PS1). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change (p.Gly12Val, p.Gly12Ala, p.Gly12Glu, p.Gly12Cys) at the same codon has been reported as pathogenic (ClinVar ID: VCV000012600.3, VCV000040430.1, VCV000163690.1, VCV000012613.12, PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.781, 3Cnet: 0.996, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813189	SCV002060958	likely pathogenic	Noonan syndrome and Noonan-related syndrome	2017-07-06	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000038460	SCV002767369	pathogenic	Costello syndrome	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Costello syndrome (MIM#218040) (PMID: 31222966). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been found in at least ten Costello syndrome patients, including reports of de novo events (PMID: 22926243, 26916728, 27102959; ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000013446	SCV000033693	pathogenic	Costello syndrome, severe	2012-06-10	no assertion criteria provided	literature only
OMIM	RCV000029210	SCV000051856	pathogenic	Nevus sebaceous	2012-06-10	no assertion criteria provided	literature only
Baylor Genetics	RCV000149830	SCV000196674	pathogenic	RASopathy		no assertion criteria provided	clinical testing	Variant classified using ACMG guidelines
Database of Curated Mutations (DoCM)	RCV000429375	SCV000505662	likely pathogenic	Breast neoplasm	2015-07-14	no assertion criteria provided	literature only
Institute of Medical Sciences, Banaras Hindu University	RCV001255681	SCV001432246	pathogenic	Lip and oral cavity carcinoma	2019-04-30	no assertion criteria provided	research