ClinVar Miner

Submissions for variant NM_005343.4(HRAS):c.401C>T (p.Ala134Val)

dbSNP: rs397517141
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000038463 SCV000062141 uncertain significance not specified 2013-11-11 criteria provided, single submitter clinical testing The Ala134Val variant in HRAS has not been reported in the literature or in larg e population studies, but has been identified in one affected son and his unaffe cted mother by our laboratory. A different variant causing a change at this sam e residue, Ala134Ser, has been reported in one individual with acute lymphoblast ic leukemia (ALL, COSMIC database), which may suggest that a change at this amin o acid position is not tolerated. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Ala1 34Val variant may impact the protein. However, this information is not enough to assume pathogenicity. In summary, additional information is needed to fully ass ess the clinical significance of the Ala134Val variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV000230783 SCV000288858 uncertain significance Costello syndrome 2023-10-22 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 134 of the HRAS protein (p.Ala134Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HRAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 45303). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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