ClinVar Genomic variation as it relates to human health

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.

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hearing loss who had two clinic ally significant variants in another gene that likely explained the hearing loss (LMM unpublished data).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.

Not observed at a significant frequency in large population cohorts (gnomAD); 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: 31412945, 32860223, 28566687, 34868270, 35682719)

Variant summary: TMPRSS3 c.1343T>C (p.Met448Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251392 control chromosomes (gnomAD). c.1343T>C has been reported in the literature in multiple individuals affected with Deafness, Autosomal Recessive 8 (e.g. Lechowicz_2017). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 28566687). ClinVar contains an entry for this variant (Variation ID: 46104). Based on the evidence outlined above, the variant was classified as pathogenic.

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.