Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000157917 | SCV000207852 | pathogenic | not provided | 2018-06-25 | criteria provided, single submitter | clinical testing | The G60D variant has been reported in multiple individuals, including apparently de novo occurrences, in association with attenuated Costello syndrome (Gripp et al., 2015). The G60D variant is not observed in large population cohorts (Lek et al., 2016). The G60D 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. Other pathogenic missense variants in this residue in other RAS genes (KRAS: G60S/R/V; NRAS: G60R/E) have been reported in the Human Gene Mutation Database in association with RASopathies (Stenson et al., 2014). This variant is interpreted to be pathogenic. |
Labcorp Genetics |
RCV001387769 | SCV001588484 | pathogenic | Costello syndrome | 2022-05-04 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This variant disrupts the p.Gly60 amino acid residue in HRAS. Other variant(s) that disrupt this residue have been observed in individuals with HRAS-related conditions (PMID: 28027064), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects HRAS function (PMID: 28139825). 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. ClinVar contains an entry for this variant (Variation ID: 40436). This missense change has been observed in individual(s) with clinical features of Costello and Noonan syndrome (PMID: 25914166, 26467218, 28139825, 30732632). In at least one individual the variant was observed to be de novo. This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 60 of the HRAS protein (p.Gly60Asp). For these reasons, this variant has been classified as Pathogenic. |
Mayo Clinic Laboratories, |
RCV000157917 | SCV005413959 | pathogenic | not provided | 2024-07-29 | criteria provided, single submitter | clinical testing | PP3, PM2, PM6_strong, PS3, PS4_moderate |