Submissions for variant NM_138691.3(TMC1):c.1333C>T (p.Arg445Cys)

gnomAD frequency: 0.00005  dbSNP: rs372710475

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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The Arg445Cys variant in TMC1 has been reported in 5 families with hearing loss (Sirmaci 2009, Ganapathy 2014, LMM unpublished data).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.
Eurofins Ntd Llc (ga)	RCV000407406	SCV000333397	uncertain significance	not provided	2016-05-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778889	SCV000915292	uncertain significance	Autosomal recessive nonsyndromic hearing loss 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.
Athena Diagnostics	RCV000407406	SCV001146195	likely pathogenic	not provided	2019-02-20	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Strong co-segregation with disease in affected and unaffected individuals, but from a single family.
Illumina Laboratory Services, Illumina	RCV001166638	SCV001329033	likely benign	Autosomal dominant nonsyndromic hearing loss 36	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx	RCV000407406	SCV001802982	uncertain significance	not provided	2024-02-08	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: 26186295, 26226225, 24933710, 28862181, 31980526, 35640668, 34758253, 33205915, 24416283, 19187973, 34523024, 36597107)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317102	SCV004020377	pathogenic	Nonsyndromic genetic hearing loss	2023-06-20	criteria provided, single submitter	clinical testing	Variant summary: TMC1 c.1333C>T (p.Arg445Cys) 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 7.2e-05 in 251326 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TMC1 causing Nonsyndromic Hearing Loss And Deafness, Type 7 (7.2e-05 vs 0.0011), allowing no conclusion about variant significance. c.1333C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with Nonsyndromic Hearing Loss And Deafness (e.g. Sirmaci_2009, Ganapathy_2014, Nishio_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24416283, 34523024, 30303587, 19187973). Five ClinVar submitters have assessed this variant since 2014: one classified the variant as likely benign, three as uncertain significance, and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000407406	SCV004294323	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 445 of the TMC1 protein (p.Arg445Cys). This variant is present in population databases (rs372710475, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive deafness (PMID: 19187973, 24416283). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 179070). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291365	SCV001479839	likely pathogenic	Hearing loss, autosomal recessive		no assertion criteria provided	research
Genomics England Pilot Project, Genomics England	RCV001166638	SCV001760239	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 36		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535003	SCV004120266	pathogenic	TMC1-related disorder	2023-12-14	no assertion criteria provided	clinical testing	The TMC1 c.1333C>T variant is predicted to result in the amino acid substitution p.Arg445Cys. This variant was reported in the homozygous or compound heterozygous state in multiple patients with hearing loss (Sirmaci et al. 2009. PubMed ID: 19187973; Ganapathy et al. 2014. PubMed ID: 24416283; Nishio et al. 2022. PubMed ID: 34523024). This variant is reported in 0.016% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic.