ClinVar Genomic variation as it relates to human health

The Arg216His variant has not been reported in the literature nor previously ide ntified by our laboratory. However, two similar variants (Arg216Leu and Arg216Cy s) have been identified in homozygosity or compound heterozygosity in two famili es with sensorineural hearing loss and LOD scores of 0.7 and 2.5 (Wattenhofer 20 05, Elbracht 2007). In addition, 393 controls (786 chromosomes) were tested for variants at Arg216 and none were identified. Arg216 occurs at a conserved sequen ce specific protein cleavage site that has been shown to be required for activat ion of the TMPRSS3 protein, and variants at this position have resulted in an ab sence of activated protein (Lee 2003, Wattenhofer 2005). In summary, due to the functional conservation of Arg216, the presence of other pathogenic variants at this position, and its absence in controls, the Arg216His variant is likely to b e pathogenic.

Not observed at 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: 31589614, 26445815)

Variant summary: TMPRSS3 c.647G>A (p.Arg216His) results in a non-conservative amino acid change located in the Serine proteases, trypsin domain (IPR001254) of 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 8e-06 in 251346 control chromosomes (gnomAD). c.647G>A has been reported in the literature in at-least one individual affected with non-syndromic hearing loss (Sloan-Heggen_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Different variant affecting the same residue (p.Arg216Cys) has been classified pathogenic internally. The following publication has been ascertained in the context of this evaluation (PMID: 26445815). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 216 of the TMPRSS3 protein (p.Arg216His). This variant is present in population databases (rs137853000, gnomAD 0.01%). This missense change has been observed in individual(s) with deafness (PMID: 26445815). ClinVar contains an entry for this variant (Variation ID: 46127). 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%. This variant disrupts the p.Arg216 amino acid residue in TMPRSS3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17551081, 34440452). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.