ClinVar Miner

Submissions for variant NM_138691.2(TMC1):c.1236del (p.Met413fs) (rs876657727)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413125 SCV000491583 pathogenic not provided 2016-10-12 criteria provided, single submitter clinical testing The c.1236delT pathogenic variant in the TMC1 gene has not been published previously as a pathogenic variant, nor as a benign variant, to our knowledge. It is reported as a pathogenic variant in ClinVar by a different clinical laboratory and was identified in the compound heterozygous state with another truncating variant in an individual with hearing loss (ClinVar SCV000271462.1; Landrum et al., 2015). The c.1236delT variant causes a frameshift starting with codon Methionine 413, changes this amino acid to a Cysteine residue, and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Met413CysfsX4. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1236delT variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1236delT as a pathogenic variant.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000217598 SCV000271462 pathogenic Rare genetic deafness 2015-06-04 criteria provided, single submitter clinical testing The p.Met413fs variant in TMC1 has been previously reported in one individual wi th hearing loss by our laboratory who was compound heterozygous for this variant and a second truncating variant in TMC1 (LMM unpublished data). This variant is absent from large population studies. This frameshift variant is predicted to a lter the protein's amino acid sequence beginning at position 413 and lead to a p remature termination codon 4 amino acids downstream. This alteration is then pre dicted to lead to a truncated or absent protein. Loss of function variants affec ting both copies of TMC1 is an established disease mechanism for nonsyndromic au tosomal recessive hearing loss. In summary, this variant meets our criteria to b e classified as pathogenic for hearing loss in an autosomal recessive manner bas ed upon the predicted impact of the variant.

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