ClinVar Miner

Submissions for variant NM_016239.4(MYO15A):c.6580C>T (p.Arg2194Trp)

gnomAD frequency: 0.00011  dbSNP: rs773551819
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001729610 SCV003474715 uncertain significance not provided 2024-10-22 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2194 of the MYO15A protein (p.Arg2194Trp). This variant is present in population databases (rs773551819, gnomAD 0.03%). This missense change has been observed in individual(s) with deafness (PMID: 29907799; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 417946). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MYO15A protein function with a negative predictive value of 95%. 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.
GeneDx RCV001729610 SCV003933430 likely pathogenic not provided 2025-04-10 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29907799)
Division of Human Genetics, Children's Hospital of Philadelphia RCV000477772 SCV000536903 uncertain significance Autosomal recessive nonsyndromic hearing loss 3 2016-06-29 no assertion criteria provided research
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001729610 SCV001980251 uncertain significance not provided no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004745419 SCV005360898 uncertain significance MYO15A-related disorder 2024-06-17 no assertion criteria provided clinical testing The MYO15A c.6580C>T variant is predicted to result in the amino acid substitution p.Arg2194Trp. This variant was reported in trans to a pathogenic premature termination variant in two siblings with hearing loss, although a second missense variant was also present in cis with this variant (Sheppard et al. 2018. PubMed ID: 29907799). This variant is reported in 0.040% of alleles in individuals of European (Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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