ClinVar Genomic variation as it relates to human health

The R109Q variant in the TMPRSS3 gene has been reported previously in the compound heterozygous state in an individual with moderate non-syndromic hearing loss (Gu et al., 2015). The R109Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A different missense variant at this residue (R109W) has been reported in the Human Gene Mutation Database in association with non-syndromic hearing loss (Stenson et al., 2014), supporting the functional importance of this region of the protein. The R109Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret R109Q as a likely pathogenic variant.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

The TMPRSS3 c.326G>A variant is predicted to result in the amino acid substitution p.Arg109Gln. This variant was reported in the compound heterozygous state in a patient with non-syndromic hearing loss (Gu et al 2015. PubMed ID: 24853665). This variant is reported in 0.037% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/21-43808632-C-T). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 109 of the TMPRSS3 protein (p.Arg109Gln). This variant is present in population databases (rs139484231, gnomAD 0.03%). This missense change has been observed in individual(s) with sensorineural deafness (PMID: 24853665; Invitae). 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: 197857). 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 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg109 amino acid residue in TMPRSS3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11424922, 12920079, 28566687). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.