Submissions for variant NM_001256317.3(TMPRSS3):c.325C>T (p.Arg109Trp)

gnomAD frequency: 0.00010  dbSNP: rs201632198

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211860	SCV000063035	pathogenic	Rare genetic deafness	2013-03-01	criteria provided, single submitter	clinical testing	The Arg109Trp variant in TMPRSS3 has been reported in one family with hearing lo ss in which the variant segregated with disease (homozygous) in 3 affected and w as heterozygous in 5 unaffected family members, and was absent from 159 controls (318 chromosomes) (Ben-Yosef 2001). Our laboratory has also identified this var iant as a compound heterozygote with other pathogenic mutations in two probands with hearing loss. And finally, two studies have reported that the Arg109Trp var iant leads to a protein product that is only partially active (Guipponi 2002, An dreasen 2006). In summary, this variant meets our criteria to be classified as p athogenic.
Eurofins Ntd Llc (ga)	RCV000332878	SCV000231180	pathogenic	not provided	2014-08-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000332878	SCV000329939	pathogenic	not provided	2023-08-18	criteria provided, single submitter	clinical testing	Identified with a second variant in additional patients with sensorineural hearing loss in published literature (Lechowicz et al., 2017); Published functional studies demonstrate a damaging effect due to failure to undergo proteolytic cleavage and activate the epithelial sodium channel (Guipponi et al., 2002; Lee et al., 2003; Andreasen et al., 2006); 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: 12393794, 28246597, 12920079, 11424922, 16524950, 29937438, 28566687, 18928407, 29072634, 24526180, 31589614, 32860223, 34426522, 34868270, 36871673, 23958653, 35961784)
Illumina Laboratory Services, Illumina	RCV000262015	SCV000436176	uncertain significance	Autosomal recessive nonsyndromic hearing loss 8	2017-04-27	criteria provided, single submitter	clinical testing	The TMPRSS3 c.325C>T (p.Arg109Trp) variant has been reported in one consanguineous family with autosomal recessive hearing loss, and the variant segregated with disease in three affected homozygote individuals and 5 heterozygous obligate carriers (Ben-Yosef et al. 2001). The p.Arg109Trp variant was absent from 318 controls and is reported at a frequency of 0.00016 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in Xenopus oocytes and yeast demonstrated that the p.Arg109Trp variant leads to a protein product that fails to undergo proteolytic cleavage and is therefore only partially active (Guipponi et al. 2002; Lee et al. 2003; Andreasen et al. 2006). Based on the evidence, the p.Arg109Trp variant is classified as a likely pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Fulgent Genetics, Fulgent Genetics	RCV000332878	SCV000611325	pathogenic	not provided	2017-05-18	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000332878	SCV001448946	pathogenic	not provided	2019-07-03	criteria provided, single submitter	clinical testing
Invitae	RCV000332878	SCV002235999	pathogenic	not provided	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 109 of the TMPRSS3 protein (p.Arg109Trp). This variant is present in population databases (rs201632198, gnomAD 0.2%). This missense change has been observed in individual(s) with deafness (PMID: 11424922). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 46114). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TMPRSS3 function (PMID: 12920079). This variant disrupts the p.Arg109 amino acid residue in TMPRSS3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24853665; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
3billion	RCV000262015	SCV004013608	pathogenic	Autosomal recessive nonsyndromic hearing loss 8		criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.012%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12393794, 23958653). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.77; 3Cnet: 0.47). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000046114 / PMID: 11424922). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 11424922, 28566687). A different missense change at the same codon (p.Arg109Gln) has been reported to be associated with TMPRSS3 related disorder (PMID: 24853665). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.