ClinVar Miner

Submissions for variant NM_138691.3(TMC1):c.1233G>A (p.Met411Ile)

gnomAD frequency: 0.00001  dbSNP: rs184603559
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Total submissions: 3
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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 RCV000152037 SCV000200623 likely benign not specified 2013-09-07 criteria provided, single submitter clinical testing Met411Ile in exon 16 of TMC1: This variant is not expected to have clinical sign ificance because it has been identified in 1.6% (3/192) of Luhya Kenyan chromoso mes by the 1000 Genomes Project (dbSNP rs184603559)
GeneDx RCV001753541 SCV001997123 uncertain significance not provided 2019-12-17 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV001753541 SCV002932291 uncertain significance not provided 2023-12-11 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 411 of the TMC1 protein (p.Met411Ile). This variant is present in population databases (rs184603559, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TMC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 165434). 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 not expected to disrupt TMC1 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.

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