Submissions for variant NM_001256317.3(TMPRSS3):c.1148T>A (p.Met383Lys)

gnomAD frequency: 0.00002  dbSNP: rs749798053

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV001095708	SCV001251530	uncertain significance	Autosomal recessive nonsyndromic hearing loss 8		criteria provided, single submitter	research	The TMPRSS3 c.1151T>A (p.M384K) missense variant has not been previously reported in individuals with hearing loss, and therefore has uncertain clinical significance.
GeneDx	RCV001544971	SCV001764204	uncertain significance	not provided	2021-02-10	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV001544971	SCV002317639	likely pathogenic	not provided	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 384 of the TMPRSS3 protein (p.Met384Lys). This variant is present in population databases (rs749798053, gnomAD 0.005%). This missense change has been observed in individual(s) with deafness (PMID: 3285355, 32853555, 36633841). 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: 873474). 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 observed in individuals with TMPRSS3-related conditions (PMID: 28695016), which suggests that this may be a clinically significant amino acid residue. 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.
King Laboratory, University of Washington	RCV001095708	SCV003844182	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2023-02-28	criteria provided, single submitter	research	This variant occurred in compound heterozygosity with a TMPRSS3 frameshift variant in two siblings with bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). These siblings’ family has no other history of hearing loss. This variant is a missense at a completely conserved site and is predicted to be damaging by multiple in-silico tools. As of January 2023, this variant has been reported to ClinVar as a variant of unknown significance and is found in 5 heterozygotes on gnomAD. Based on consistently predicted functional effect, compound heterozygosity with a loss-of-function variant, co-segregation with the phenotype in the family, and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic.