Submissions for variant NM_138691.3(TMC1):c.543T>G (p.Phe181Leu)

gnomAD frequency: 0.00001  dbSNP: rs989635871

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825471	SCV000966772	uncertain significance	not specified	2019-06-11	criteria provided, single submitter	clinical testing	The p.Phe181Leu variant in TMC1 has been identified in 1 individual with hearing loss, and segregated in 5 affected relatives; however 2 non-segregations were observed in 2 affected relatives who were negative for the variant. It has been identified in 0.002% (3/113664) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, due to the conflicting segregation evidence, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PP1, BS4.
PreventionGenetics, part of Exact Sciences	RCV003413665	SCV004117200	uncertain significance	TMC1-related condition	2023-06-13	criteria provided, single submitter	clinical testing	The TMC1 c.543T>G variant is predicted to result in the amino acid substitution p.Phe181Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-75366773-T-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.