ClinVar Miner

Submissions for variant NM_138691.3(TMC1):c.821C>T (p.Pro274Leu)

gnomAD frequency: 0.00002  dbSNP: rs755694066
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV001526647 SCV001737078 pathogenic Hearing impairment criteria provided, single submitter clinical testing
GeneDx RCV001581178 SCV001811798 uncertain significance not provided 2021-06-28 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: 16287143, 19187973, 24933710, 18616530, 26226225, 27535533)
Genome-Nilou Lab RCV001658237 SCV001875865 pathogenic Autosomal recessive nonsyndromic hearing loss 7 2021-07-30 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001581178 SCV004294321 pathogenic not provided 2023-10-22 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 274 of the TMC1 protein (p.Pro274Leu). This variant is present in population databases (rs755694066, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 16287143). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1172666). 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 TMC1 protein function. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004587173 SCV005077164 pathogenic Nonsyndromic genetic hearing loss 2024-04-19 criteria provided, single submitter clinical testing Variant summary: TMC1 c.821C>T (p.Pro274Leu) 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 1.6e-05 in 251384 control chromosomes (gnomAD). c.821C>T has been reported in the literature in several homozygous individuals affected with Nonsyndromic Hearing Loss And Deafness, Type 7 (e.g. Kalay_2005). These data indicate that the variant is very likely to be associated with disease. ClinVar contains an entry for this variant (Variation ID: 1172666). Based on the evidence outlined above, the variant was classified as pathogenic.

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