Submissions for variant NM_138691.3(TMC1):c.1114G>A (p.Val372Met)

gnomAD frequency: 0.00006  dbSNP: rs367924428

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000268431	SCV000341816	likely pathogenic	not provided	2018-04-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778151	SCV000914283	uncertain significance	Autosomal recessive nonsyndromic hearing loss 7	2019-04-05	criteria provided, single submitter	clinical testing	The TMC1 c.1114G>A (p.Val372Met) missense variant has been reported in at least four studies, in which it is found in a homozygous state in four families with recessive nonsyndromic hearing loss, including three from Pakistan and one from India (Santos et al. 2005; Ganapathy et al. 2014; Shafique et al. 2014). The number of affected individuals in each family is not clear from the literature. At least one family is consanguineous. The p.Val372Met variant was absent from 234 control chromosomes but is reported at a frequency of 0.000301 in the South Asian population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Val372Met variant is therefore 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000268431	SCV002312010	likely pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 372 of the TMC1 protein (p.Val372Met). This variant is present in population databases (rs367924428, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive nonsyndromic deafness (PMID: 16134132, 24416283, 24949729). ClinVar contains an entry for this variant (Variation ID: 287884). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TMC1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV000268431	SCV005081198	uncertain significance	not provided	2023-11-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26226225, 16134132, 24416283, 24949729)
Fulgent Genetics, Fulgent Genetics	RCV005049518	SCV005679361	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 7; Autosomal dominant nonsyndromic hearing loss 36	2024-04-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005238851	SCV005888052	pathogenic	Nonsyndromic genetic hearing loss	2025-01-20	criteria provided, single submitter	clinical testing	Variant summary: TMC1 c.1114G>A (p.Val372Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251238 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TMC1 causing Nonsyndromic Hearing Loss And Deafness, Type 7 (5.6e-05 vs 0.0011), allowing no conclusion about variant significance. c.1114G>A has been reported in the literature in multiple individuals affected with Nonsyndromic Hearing Loss And Deafness, Type 7 (example, Rehman_2014, Shafique_2014). 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: 25491636, 24949729). ClinVar contains an entry for this variant (Variation ID: 287884). Based on the evidence outlined above, the variant was classified as pathogenic.
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291360	SCV001479834	likely pathogenic	Hearing loss, autosomal recessive		no assertion criteria provided	research