Submissions for variant NM_001256317.3(TMPRSS3):c.1340T>C (p.Met447Thr)

gnomAD frequency: 0.00001  dbSNP: rs201018751

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039341	SCV000063025	likely pathogenic	Rare genetic deafness	2015-10-24	criteria provided, single submitter	clinical testing	The p.Met448Thr variant in TMPRSS3 has been identified by our laboratory in 1 Ca ucasian individual with congenital sensorineural hearing loss who had two clinic ally significant variants in another gene that likely explained the hearing loss (LMM unpublished data). This variant has also been identified in 2/66540 Europe an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs201018751); however its frequency is low enough to be consiste nt with a recessive carrier frequency. Computational prediction tools and conser vation analysis do not provide strong support for or against an impact to the pr otein. The presence of this variant in trans with a second variant in TMPRSS3 an d the segregation of the two variants in an affected sibling with hearing loss i ncreases the likelihood that the p.Met448Thr variant is pathogenic. In summary, although additional studies are required to fully establish its clinical signifi cance, this variant is likely pathogenic.
Illumina Laboratory Services, Illumina	RCV001140597	SCV001300869	uncertain significance	Autosomal recessive nonsyndromic hearing loss 8	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV001559611	SCV001781877	likely pathogenic	not provided	2020-10-02	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32860223, 31412945, 28566687)
Institute of Human Genetics, University of Leipzig Medical Center	RCV001140597	SCV001950040	uncertain significance	Autosomal recessive nonsyndromic hearing loss 8	2021-08-11	criteria provided, single submitter	clinical testing
Invitae	RCV001559611	SCV003444512	pathogenic	not provided	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 448 of the TMPRSS3 protein (p.Met448Thr). This variant is present in population databases (rs201018751, gnomAD 0.004%). This missense change has been observed in individual(s) with nonsyndromic deafness (PMID: 28566687, 31412945, 32860223). 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: 46104). 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 TMPRSS3 protein function. Studies have shown that this missense change alters TMPRSS3 gene expression (PMID: 28566687). For these reasons, this variant has been classified as Pathogenic.