Submissions for variant NM_001256317.3(TMPRSS3):c.325C>T (p.Arg109Trp) (rs201632198)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Partners HealthCare 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000332878	SCV000231180	pathogenic	not provided	2014-08-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000332878	SCV000329939	pathogenic	not provided	2021-09-23	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; Splice predictors and evolutionary conservation are inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 12393794, 28246597, 12920079, 11424922, 16524950, 29937438, 28566687, 18928407, 29072634, 24526180, 31589614, 32860223)
Illumina Clinical Services Laboratory,Illumina	RCV000262015	SCV000436176	uncertain significance	Deafness, autosomal recessive 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