ClinVar Miner

Submissions for variant NM_016239.4(MYO15A):c.4898T>C (p.Ile1633Thr)

gnomAD frequency: 0.00001  dbSNP: rs576399072
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Total submissions: 4
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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 RCV001195238 SCV001365545 uncertain significance not specified 2019-08-12 criteria provided, single submitter clinical testing The p.Ile1633Thr variant in MYO15A has been previously reported in 1 individual with hearing loss, who harbored a second variant in MYO15A, though phase was not confirmed (Gu 2015). It has been identified in 0.01% (2/17976) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2_Supporting.
Molecular Diagnosis Center for Deafness RCV002224975 SCV001984911 likely pathogenic Autosomal recessive nonsyndromic hearing loss 3 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003558750 SCV004298147 uncertain significance not provided 2023-11-07 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1633 of the MYO15A protein (p.Ile1633Thr). This variant is present in population databases (rs576399072, gnomAD 0.01%). This missense change has been observed in individuals with deafness (PMID: 24853665, 27375115, 35346193, 35982127). ClinVar contains an entry for this variant (Variation ID: 929901). 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 80%. 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.
Juno Genomics, Hangzhou Juno Genomics, Inc RCV002224975 SCV005417038 uncertain significance Autosomal recessive nonsyndromic hearing loss 3 criteria provided, single submitter clinical testing PM2_Supporting+PP3+PM3_Supporting

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