ClinVar Miner

Submissions for variant NM_138691.2(TMC1):c.1333C>T (p.Arg445Cys) (rs372710475)

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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,Partners HealthCare Personalized Medicine RCV000155854 SCV000205565 likely pathogenic Rare genetic deafness 2014-07-09 criteria provided, single submitter clinical testing The Arg445Cys variant in TMC1 has been reported in 5 families with hearing loss (Sirmaci 2009, Ganapathy 2014, LMM unpublished data). In one family, the varian t is homozygous in 3 siblings with nonsyndromic autosomal recessive sensorineura l hearing loss and heterozygous in 4 unaffected relatives (Sirmaci 2009). In an other family, it is homozygous in two affected individuals (Ganapathy 2014). Th is variant has been identified in 0.01% (1/8600) of European American chromosome s by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS/). Alt hough this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In addition, comput ational prediction tools and conservation analyses suggest that the Arg445Cys va riant may impact the protein, though this information is not predictive enough t o determine pathogenicity. In summary, this variant is likely to be pathogenic, though additional studies are required to fully establish its clinical significa nce.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000407406 SCV000333397 uncertain significance not provided 2016-05-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778889 SCV000915292 uncertain significance Deafness, autosomal recessive 7 2019-01-10 criteria provided, single submitter clinical testing The TMC1 c.1333C>T (p.Arg445Cys) variant has been reported in three studies and is found in four individuals in a homozygous state, including three affected siblings from a consanguineous family, and in one proband in a compound heterozygous state (Sirmaci et al. 2009; Ganapathy et al. 2014; Gao et al. 2016). This variant is also found in five unaffected relatives in a heterozygous state (Sirmaci et al. 2009; Gao et al. 2016). The p.Arg445Cys variant was absent from 302 control chromosomes (Sirmaci et al. 2009; Ganapathy et al. 2014) and is reported at a frequency of 0.00035 in the East Asian population of the Exome Aggregation Consortium. The variant is present in a transmembrane region of the TMC1 protein. The arginine residue at position 445 is highly conserved (Sirmaci et al. 2009). Based on the evidence, the p. Arg445Cys variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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