ClinVar Miner

Submissions for variant NM_138691.3(TMC1):c.1165C>T (p.Arg389Ter)

gnomAD frequency: 0.00006  dbSNP: rs151001642
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Total submissions: 7
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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 RCV000041126 SCV000064817 pathogenic Rare genetic deafness 2013-09-05 criteria provided, single submitter clinical testing The Arg389X variant in TMC1 has been reported in several individual with hearing loss (Hilgert 2008, Meyer 2005, Tlili 2008). All of these individuals were eith er homozygous or compound heterozygous and this variant segregated with hearing loss in several families. This nonsense variant leads to a premature termination codon at position 389, which is predicted to lead to a truncated or absent prot ein. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).
Eurofins Ntd Llc (ga) RCV000596838 SCV000705004 pathogenic not provided 2017-01-17 criteria provided, single submitter clinical testing
Athena Diagnostics RCV000596838 SCV001474920 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 RCV000596838 SCV001581540 pathogenic not provided 2024-02-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg389*) 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 (rs151001642, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with autosomal recessive non-syndromic hearing loss (PMID: 15605408, 18259073, 21917145). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 47856). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000596838 SCV001770346 pathogenic not provided 2025-02-06 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: 25525159, 15605408, 18259073, 31589614, 25560255, 29533536, 34523024, 33879512, 33352559, 21917145, 18616530, 34599366)
Clinical Genomics Laboratory, Washington University in St. Louis RCV004555851 SCV005045051 pathogenic Autosomal recessive nonsyndromic hearing loss 7 2024-01-25 criteria provided, single submitter clinical testing The TMC1 c.1165C>T (p.Arg389Ter) variant has been reported in 19 individuals affected with autosomal recessive nonsyndromic hearing loss and is reported to segregate with disease in 14 individuals in 4 families (Brownstein Z et al., PMID: 21917145; Hilgert N et al., PMID: 18616530; Meyer CG et al., PMID: 15605408; Nishio SY and Usami SI, PMID: 34523024; Tlili A et al., PMID: 18259073). Of those individuals, seven were compound heterozygous for the variant and a pathogenic or likely pathogenic variant, confirmed in trans (Brownstein Z et al., PMID: 21917145; Meyer CG et al., PMID: 15605408) and 12 individuals were homozygous for the variant (Hilgert N et al., PMID: 18616530; Meyer CG et al., PMID: 15605408; Nishio SY and Usami SI, PMID: 34523024). This variant causes a stop gain, leading to a premature termination codon, which is predicted to lead to nonsense mediated decay. This variant is only observed on 19 out of 282,746 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant has been reported in the ClinVar database as a germline pathogenic variant by five submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV005042115 SCV005679362 pathogenic Autosomal recessive nonsyndromic hearing loss 7; Autosomal dominant nonsyndromic hearing loss 36 2024-02-06 criteria provided, single submitter clinical testing

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