ClinVar Genomic variation as it relates to human health

The p.Gly243Arg variant in TMPRSS3 has been reported in one Indian individual wi th hearing loss (Ganapathy 2014). The variant was detected in the homozygous sta te in the proband and in two affected siblings, and the parents who were heteroz ygous carriers were unaffected (Ganapathy 2014). In addition the variant has bee n previously detected in the homozygous state by our laboratory in one individua l with profound sensorineural hearing loss (this individual's son). The p.Gly243 Arg variant has been identified in 1/8600 European American chromosomes by the N HLBI Exome Sequencing Project and in 3/16618 South Asian chromosomes by the Exom e Aggregation Consortium (http://evs.gs.washington.edu/EVS/; http://exac.broadin stitute.org; dbSNP rs372526764). Although this variant has been seen in the gene ral population, its frequency is low enough to be consistent with a recessive ca rrier frequency. Computational prediction tools and conservation analyses sugges t that the p.Gly243Arg variant may impact the protein, though this information i s not predictive enough to determine pathogenicity. In summary, although additio nal studies are required to fully establish its clinical significance, this vari ant is likely pathogenic.

The TMPRSS3 c.727G>A variant is predicted to result in the amino acid substitution p.Gly243Arg. This variant is located in the highly conserved catalytic serine protease domain, and was reported in the homozygous state in three siblings with autosomal recessive non-syndromic deafness (Ganapathy et al. 2014. PubMed ID: 24416283). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/21-43803197-C-T). This variant is interpreted as likely pathogenic.

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 243 of the TMPRSS3 protein (p.Gly243Arg). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 178549). This missense change has been observed in individual(s) with deafness (PMID: 24416283). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs372526764, gnomAD 0.01%).

TMPRSS3: PM2, PM3, PP1:Moderate

Variant summary: TMPRSS3 c.727G>A (p.Gly243Arg) 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 2.8e-05 in 251270 control chromosomes (gnomAD). c.727G>A has been reported in the literature in multiple individuals affected with Deafness, Autosomal Recessive 8 (e.g. Ganapathy_2014, Khan_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 24416283, 31389194). ClinVar contains an entry for this variant (Variation ID: 178549). Based on the evidence outlined above, the variant was classified as pathogenic.

12 years old child with deafness and a history of parental consanguinity. Next generation DNA sequencing of peripheral blood sample has revealed presence of a homozygous variant c.727 G>A in exon 8 of TMPRSS3 gene. This variant was predicted to be likely pathogenic based on available evidences in the databases and in silico mutation prediction methods.