Submissions for variant NM_005343.4(HRAS):c.38G>A (p.Gly13Asp)

dbSNP: rs104894226

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000157913	SCV000207848	pathogenic	not provided	2023-08-28	criteria provided, single submitter	clinical testing	Published functional studies demonstrate aberrant RAS pathway activity (Niihori et al., 2011; Wey et al., 2013); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24803665, 24224811, 23751039, 23093928, 23487764, 28371260, 28425981, 30050098, 29907801, 32732226, 33726816, 34958143, 34906519, 21850009, 16170316)
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000013438	SCV000263058	pathogenic	Costello syndrome	2014-06-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781469	SCV000919526	pathogenic	RASopathy	2018-01-15	criteria provided, single submitter	clinical testing	Variant summary: The HRAS c.38G>A (p.Gly13Asp) variant involves the alteration of a highly conserved nucleotide. The variant is located within the GTP/Mg2+ binding site in the conserved domain of Ras GTPase. 4/5 in silico tools predict a damaging outcome for this variant and it was experimentally confirmed to cause activation of RAS in vitro. This variant is absent from control dataset of gnomAD (~276492 chrs tested), but was identified in several Costello patients as a de novo event (Aoki_2005; Schulz _2008). The Gly13 codon appears to be a mutational hotspot, as other alterations, such as G13V and G13C, have been reported in patients with Costello Syndrome. Taken together, this variant is classified as Pathogenic.
Invitae	RCV000013438	SCV001212308	pathogenic	Costello syndrome	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 13 of the HRAS protein (p.Gly13Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Costello syndrome (PMID: 28371260). ClinVar contains an entry for this variant (Variation ID: 12604). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HRAS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HRAS function (PMID: 21850009). This variant disrupts the p.Gly13 amino acid residue in HRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16329078, 18042262, 21438134). 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	RCV000157913	SCV001370940	pathogenic	not provided	2021-07-01	criteria provided, single submitter	clinical testing
Genomic Medicine Lab, University of California San Francisco	RCV001376018	SCV001573028	pathogenic	Non-immune hydrops fetalis	2020-06-18	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813187	SCV002060966	pathogenic	Noonan syndrome and Noonan-related syndrome	2016-12-12	criteria provided, single submitter	clinical testing
Provincial Medical Genetics Program of British Columbia, University of British Columbia	RCV000013438	SCV002320820	pathogenic	Costello syndrome	2022-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002476960	SCV002794280	pathogenic	Large congenital melanocytic nevus; Linear nevus sebaceous syndrome; Malignant tumor of urinary bladder; Costello syndrome; Epidermal nevus; Thyroid cancer, nonmedullary, 2	2022-03-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000013438	SCV004041106	pathogenic	Costello syndrome	2023-08-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003390677	SCV004121095	pathogenic	HRAS-related condition	2022-12-09	criteria provided, single submitter	clinical testing	The HRAS c.38G>A variant is predicted to result in the amino acid substitution p.Gly13Asp. This variant is reported to be causative for Costello syndrome (see for example - Aoki et al. 2005. PubMed ID: 16170316; Takahashi and Ohashi. 2013. PubMed ID: 23751039; Bertola et al. 2017. PubMed ID: 28371260). Additionally, multiple missense variants affecting this amino acid (p.Gly13Arg, p.Gly13Cys, p.Gly13Val) have been reported to be pathogenic (Human Gene Mutation Database). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
OMIM	RCV000013438	SCV000033685	pathogenic	Costello syndrome	2005-10-01	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439514	SCV000505743	not provided	Neoplasm of the large intestine	2016-03-10	no assertion provided	literature only
Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University	RCV000013438	SCV003844077	pathogenic	Costello syndrome	2022-04-02	no assertion criteria provided	research