Submissions for variant NM_005343.4(HRAS):c.37G>T (p.Gly13Cys) (rs104894228)

Total submissions: 29

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, Partners HealthCare 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	2018-05-04	criteria provided, single submitter	clinical testing	The G13C variant in the HRAS gene has been reported previously in multiple unrelated individuals with Costello syndrome and is one of the common HRAS variants associated with this disorder (Estep et al., 2006; Gripp et al., 2006; Gripp et al., 2011). In addition to the classic Costello features, this variant has been described in patients with unique ectodermal findings such as sparse hair in early childhood and long eyelashes, and appears to have a low incidence of papillomata (Gripp et al., 2011). The G13C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G13C variant is a non-conservative amino acid substitution, which occurs at a conserved Glycine residue at codon 12; the majority of pathogenic variants in the HRAS gene (>90%) alter the conserved glycine residues at positions 12 and 13 (Aoki et al., 2005; Gripp et al., 2006). 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). Therefore, we interpret G13C as a pathogenic variant.
Invitae	RCV000013440	SCV000259986	pathogenic	Costello syndrome	2018-08-10	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with cysteine at codon 13 of the HRAS protein (p.Gly13Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. This variant is not present in population databases and has been reported in multiple individuals with Costello syndrome (PMID: 16372351, 21438134, 18042262, 16329078). ClinVar contains an entry for this variant (RCV000013440, RCV000149831). Experimental studies in vitro have found that this missense change constitutively activates RAS signaling and speeds up the cellular aging process, consistent with other well characterized deleterious mutations in this region of the HRAS protein (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 Alfred I. duPont Hospital for Children	RCV000207504	SCV000263057	pathogenic	not provided	2014-06-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000013440	SCV000807270	pathogenic	Costello syndrome	2017-09-01	criteria provided, single submitter	clinical testing	This same amino acid substitution has been previously reported as disease-causing and was found once in our laboratory de novo in a newborn female with prematurity, non-immune fetal hydrops, mild microcytic anemia, 2 muscular apical VSDs, large PDA and PFO, cup-shaped ears, hypotonia
Fulgent Genetics,Fulgent Genetics	RCV000762847	SCV000893207	pathogenic	Congenital giant melanocytic nevus; Epidermal nevus syndrome; Bladder cancer, somatic; Costello syndrome; Epidermal nevus; Follicular thyroid carcinoma	2018-10-31	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	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.
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
Database of Curated Mutations (DoCM)	RCV000428812	SCV000504407	pathogenic	Neoplasm of the thyroid gland	2014-10-02	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439954	SCV000504408	likely pathogenic	Neoplasm	2015-07-14	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439052	SCV000506576	likely pathogenic	Adenocarcinoma of stomach	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420958	SCV000506577	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431688	SCV000506578	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441514	SCV000506579	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424247	SCV000506580	likely pathogenic	Neoplasm of the breast	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434069	SCV000506581	likely pathogenic	Chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445225	SCV000506582	likely pathogenic	Uterine cervical neoplasms	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423190	SCV000506583	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433893	SCV000506584	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445336	SCV000506585	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426653	SCV000506586	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436007	SCV000506587	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444110	SCV000506588	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425964	SCV000506589	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436205	SCV000506590	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417661	SCV000506591	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital	RCV000678903	SCV000805106	pathogenic	Noonan syndrome	2017-08-24	no assertion criteria provided	clinical testing