Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000602031 | SCV000732016 | uncertain significance | not specified | 2018-10-30 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Tyr1437Cy s variant in MYO15A has been previously reported in two individuals with hearing loss (LMM data, Sloan-Heggen 2016). One individual also harbored a pathogenic t runcating MYO15A variant (LMM data), and one individual harbored a second varian t of uncertain significance in MYO15A (Sloan-Heggen 2016). Phasing was not perfo rmed for either individual. This variant has been identified in 0.02% (3/15418) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computation al prediction tools and conservation analysis suggest that the variant may impac t the protein, though this information is not predictive enough to determine pat hogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Tyr1437Cys variant is uncertain. ACMG/AMP Criter ia applied: PM2; PP3; PM3_Supporting. |
| Molecular Diagnosis Center for Deafness | RCV002224970 | SCV001984900 | uncertain significance | Autosomal recessive nonsyndromic hearing loss 3 | criteria provided, single submitter | clinical testing | ||
| Fulgent Genetics, |
RCV002224970 | SCV002786572 | uncertain significance | Autosomal recessive nonsyndromic hearing loss 3 | 2022-02-25 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV003558473 | SCV004298141 | pathogenic | not provided | 2024-03-07 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1437 of the MYO15A protein (p.Tyr1437Cys). This variant is present in population databases (no rsID available, gnomAD 0.02%). This missense change has been observed in individual(s) with deafness (PMID: 26969326, 32279305, 35346193, 35580552). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 517638). 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. |