Submissions for variant NM_001256317.3(TMPRSS3):c.316C>T (p.Arg106Cys)

gnomAD frequency: 0.00009  dbSNP: rs139805921

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000441150	SCV000521274	likely pathogenic	not provided	2024-10-14	criteria provided, single submitter	clinical testing	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: 27627659, 23967202, 28695016, 28246597, 34426522, 31589614, 34868270, 36147510, 37331337, 38102706, 34795337, 38691166)
Eurofins Ntd Llc (ga)	RCV000441150	SCV000860265	likely pathogenic	not provided	2018-07-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000441150	SCV001246792	pathogenic	not provided	2022-09-01	criteria provided, single submitter	clinical testing	TMPRSS3: PM3:Very Strong, PM2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251375	SCV001426949	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2020-07-29	criteria provided, single submitter	clinical testing	Variant summary: TMPRSS3 c.316C>T (p.Arg106Cys) results in a non-conservative amino acid change located in the scavenger receptor cysteine-rich (SRCR) domain (IPR001190); most SRCR domains have six to eight cysteines that participate in intradomain disulfide bonds (InterPro). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 251448 control chromosomes in the gnomAD database, including 1 homozygote. The variant, c.316C>T, has been reported in the literature in individuals affected with late onset hearing loss (Gao_2017, Miyagawa_2013), including a large Chinese family, where the variant in combination with a presumed severe mutation in trans (c.916G>A (p.Ala306Thr)) resulted in a milder phenotype (Gao_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic (n=1) / likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375183	SCV001571789	likely pathogenic	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PS1_Strong, PM2_Supporting, PP3_Supporting
Labcorp Genetics (formerly Invitae), Labcorp	RCV000441150	SCV003444393	pathogenic	not provided	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 106 of the TMPRSS3 protein (p.Arg106Cys). This variant is present in population databases (rs139805921, gnomAD 0.06%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with deafness (PMID: 23967202, 28246597). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 381714). 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%. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003401420	SCV004120702	likely pathogenic	TMPRSS3-related disorder	2023-01-17	criteria provided, single submitter	clinical testing	The TMPRSS3 c.316C>T variant is predicted to result in the amino acid substitution p.Arg106Cys. This variant has been reported in individuals with late-onset hearing loss (Supplemental Table 2, Miyagawa et al. 2013. PubMed ID: 23967202). This variant has also been reported in the compound heterozygous state in individuals with post lingual, milder hearing impairments (Patients II:2, II:3, and II:5, Gao et al. 2017. PubMed ID: 28246597) and in the homozygous state in an individual with perilingual hearing loss (Pavlenkova et al. 2021. PubMed ID: 34795337). This variant is reported in 0.059% of alleles in individuals of South Asian descent in gnomAD, including one homozygous individual (http://gnomad.broadinstitute.org/variant/21-43809044-G-A). This variant is predicted to lead to a mild form of hearing loss and structural protein modeling suggesting that a homozygous p.Arg106Cys variant would lead to a subtle protein change or would be similar to that of wildtype protein (Gao et al. 2017. PubMed ID: 28246597). This variant is interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/381714/). Taken together, we interpret this variant as likely pathogenic.