Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000152060 | SCV000200680 | uncertain significance | not specified | 2013-05-15 | criteria provided, single submitter | clinical testing | The Met384Ile variant in TMPRSS3 has not been reported in individuals with heari ng loss or in large population studies. Computational analyses (biochemical amin o acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, additional d ata is needed to determine the clinical significance of this variant. |
| Invitae | RCV003546480 | SCV004268319 | likely pathogenic | not provided | 2023-12-29 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 384 of the TMPRSS3 protein (p.Met384Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TMPRSS3-related conditions. ClinVar contains an entry for this variant (Variation ID: 165482). 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.Met384 amino acid residue in TMPRSS3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 3285355, 36633841; Invitae). 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. |
| Division of Human Genetics, |
RCV000477944 | SCV000536725 | uncertain significance | Autosomal recessive nonsyndromic hearing loss 8 | 2015-03-09 | no assertion criteria provided | research |