Submissions for variant NM_001256317.3(TMPRSS3):c.1333G>A (p.Glu445Lys)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV003397454	SCV004103136	uncertain significance	TMPRSS3-related disorder	2023-08-03	criteria provided, single submitter	clinical testing	The TMPRSS3 c.1336G>A variant is predicted to result in the amino acid substitution p.Glu446Lys. This variant was reported in an individual with non-syndromic hearing loss (Charif. 2012. PubMed ID: 22382023). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/21-43795836-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Invitae	RCV003553900	SCV004297386	likely pathogenic	not provided	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 446 of the TMPRSS3 protein (p.Glu446Lys). This variant is present in population databases (rs777595673, gnomAD 0.004%). This missense change has been observed in individuals with autosomal recessive nonsyndromic deafness (PMID: 22382023). ClinVar contains an entry for this variant (Variation ID: 2631680). 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 not expected to disrupt TMPRSS3 protein function with a negative predictive value of 95%. 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.