Submissions for variant NM_001256317.3(TMPRSS3):c.743C>T (p.Thr248Met)

gnomAD frequency: 0.00001  dbSNP: rs768140716

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001822027	SCV002064160	likely pathogenic	not provided	2024-04-08	criteria provided, single submitter	clinical testing	Identified with a second TMPRSS3 variant in additional patients with sensorineural hearing loss referred for genetic testing at GeneDx and in published literature (PMID: 31581539); Published functional studies demonstrate a mild decrease in protease activity of the variant protein compared to wild-type, however it is not known if this is a functionally significant decrease (PMID: 24526180); 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: 29072634, 34868270, 24526180, 31581539, 36568422, 34416374, 34515852)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331211	SCV004039097	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2023-08-11	criteria provided, single submitter	clinical testing	Variant summary: TMPRSS3 c.743C>T (p.Thr248Met) 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 5.6e-05 in 251280 control chromosomes (gnomAD). c.743C>T has been reported in the literature in at least 4 patients affected with nonsyndromic hearing loss (e.g. Chung_2014, Kim_2021, Wu_2019, Guan_2021), where several compound heterozygotes carried a (likely) pathogenic variant in trans. These data indicate that the variant is likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated a mild decrease in protease activity (Chung_2014). The following publications have been ascertained in the context of this evaluation (PMID: 24526180, 35864128, 34416374, 31581539). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001822027	SCV004297395	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 248 of the TMPRSS3 protein (p.Thr248Met). This variant is present in population databases (rs768140716, gnomAD 0.05%). This missense change has been observed in individual(s) with nonsyndromic deafness (PMID: 24526180, 34416374). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1335824). 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 TMPRSS3 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TMPRSS3 function (PMID: 24526180). For these reasons, this variant has been classified as Pathogenic.
3billion	RCV003331211	SCV005904089	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2024-02-24	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Predicted Consequence/Location: Missense variant Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 24526180). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.81 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.34 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TMPRSS3 related disorder (ClinVar ID: VCV001335824 /PMID: 24526180). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.