ClinVar Miner

Submissions for variant NM_138691.3(TMC1):c.1676G>A (p.Trp559Ter)

gnomAD frequency: 0.00004  dbSNP: rs876657728
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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 RCV000219905 SCV000271463 pathogenic Rare genetic deafness 2016-12-22 criteria provided, single submitter clinical testing The p.Trp559X variant in TMC1 has now been identified by our laboratory in 2 ind ividuals with hearing loss, and both of them have a second pathogenic variant in TMC1. This variant has not been identified in large population studies. This no nsense variant leads to a premature termination codon at position 559, which is predicted to lead to a truncated or absent protein. Loss of function variants af fecting both copies of TMC1 is an established disease mechanism for nonsyndromic autosomal recessive hearing loss. In summary, this variant meets criteria to be classified as pathogenic for hearing loss in an autosomal recessive manner base d upon the predicted impact of the variant.
Athena Diagnostics RCV001288079 SCV001474922 pathogenic not provided 2020-07-23 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp RCV001288079 SCV004535341 pathogenic not provided 2023-12-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp559*) in the TMC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMC1 are known to be pathogenic (PMID: 11850618, 22105175). This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with congenital deafness (PMID: 29196752). ClinVar contains an entry for this variant (Variation ID: 228406). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001288079 SCV005079326 likely pathogenic not provided 2023-09-22 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29196752)

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