ClinVar Miner

Submissions for variant NM_016239.4(MYO15A):c.8375T>C (p.Val2792Ala)

gnomAD frequency: 0.00001  dbSNP: rs983107737
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Diagnosis Center for Deafness RCV001254926 SCV001332618 pathogenic Autosomal recessive nonsyndromic hearing loss 3 2020-02-27 criteria provided, single submitter case-control
Labcorp Genetics (formerly Invitae), Labcorp RCV003558740 SCV004298166 pathogenic not provided 2023-11-14 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 2792 of the MYO15A protein (p.Val2792Ala). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with deafness (PMID: 24206587, 36401330). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 915471). 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 MYO15A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004587058 SCV005075873 uncertain significance not specified 2024-04-02 criteria provided, single submitter clinical testing Variant summary: MYO15A c.8375T>C (p.Val2792Ala) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249244 control chromosomes. c.8375T>C has been reported in the literature in multiple compound heterozygous individuals from one family affected with Autosomal Recessive Nonsyndromic Hearing Loss 3 (e.g. Gao_2013, Yang_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24206587, 36401330). ClinVar contains an entry for this variant (Variation ID: 915471). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Fulgent Genetics, Fulgent Genetics RCV001254926 SCV005644778 likely pathogenic Autosomal recessive nonsyndromic hearing loss 3 2024-04-06 criteria provided, single submitter clinical testing

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