ClinVar Miner

Submissions for variant NM_005343.4(HRAS):c.38G>A (p.Gly13Asp) (rs104894226)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157913 SCV000207848 pathogenic not provided 2017-01-04 criteria provided, single submitter clinical testing The G13D missense variant in the HRAS gene has been reported previously in association with Costello syndrome (Aoki et al., 2005). The most common HRAS variants associated with Costello syndrome alter the conserved Glycine residues at positions 12 and 13 (Aoki et al., 2005; Gripp et al., 2006).
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000013438 SCV000263058 pathogenic Costello syndrome 2014-06-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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 2019-04-16 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 13 of the HRAS protein (p.Gly13Asp). 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 several individuals affected with Costello syndrome (PMID: 28371260). ClinVar contains an entry for this variant (Variation ID: 12604). This variant has been reported to affect HRAS protein function (PMID: 21850009). This variant disrupts the p.Gly13 amino acid residue in HRAS. Other variant(s) that disrupt this residue have been observed in individuals with HRAS-related conditions (PMID: 16329078, 18042262, 21438134), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified 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

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