ClinVar Miner

Submissions for variant NM_001256317.3(TMPRSS3):c.916G>A (p.Ala306Thr)

gnomAD frequency: 0.00019  dbSNP: rs181949335
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000039368 SCV000063052 pathogenic Rare genetic deafness 2019-03-12 criteria provided, single submitter clinical testing The p.Ala306Thr variant in TMPRSS3 has been reported in >10 individuals with autosomal recessive hearing loss and segregated in >10 affected relatives in >5 families (Elbracht 2007, Weegerink 2011, Schrauwen 2012, Lee 2013, Chung 2014, Gao 2017a, Gao 2017b). All affected individuals were either homozygous or compound heterozygous. This variant has also been identified in 0.06% (12/19954) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies support an impact on protein function (Chung 2014). Computational prediction tools and conservation analysis also support a functional impact. In summary, the p.Ala306Thr variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss. ACMG/AMP criteria applied: PM3_VeryStrong, PP1_Strong, PM2_Supporting, PP3, PS3_Supporting.
Eurofins Ntd Llc (ga) RCV000732326 SCV000860268 pathogenic not provided 2018-04-04 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000779355 SCV000915954 pathogenic Autosomal recessive nonsyndromic hearing loss 8 2018-09-06 criteria provided, single submitter clinical testing Across a selection of the available literature, the TMPRSS3 c.916G>A (p.Ala306Thr) variant has been identified in a homozygous state in two siblings and in a compound heterozygous state in 15 individuals from nine families with autosomal recessive hearing loss (Elbracht et al. 2007; Weegerink et al. 2011; Lee et al. 2013; Chung et al. 2014; Gao et al. 2017). The variant was also found in a heterozygous state in at least three family members with normal hearing. Co-segregation of the variant with disease was demonstrated in at least one family (Gao et al. 2017), and has been suggested to be a founder variant in the Korean population, as two families with the variant were found to share the same haplotype (Chung et al. 2014). The p.Ala306Thr variant was absent from 1770 control chromosomes and is reported at a frequency of 0.00104 in the East Asian population of the Exome Aggregation Consortium. An in vitro yeast-based protease assay showed that the p.Ala306Thr variant-containing protein exhibited significantly reduced protease activity compared to the wild type protein as well as proteins containing other missense variants, consistent with the location of the variant near the Asp304 active site (Chung et al. 2014). Based on the collective evidence, the p.Ala306Thr variant is classified as pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center RCV001375145 SCV001572103 likely pathogenic Hearing impairment 2021-04-12 criteria provided, single submitter clinical testing PS1_Strong, PM2_Moderate, PP3_Supporting
Center of Genomic medicine, Geneva, University Hospital of Geneva RCV000779355 SCV001745849 pathogenic Autosomal recessive nonsyndromic hearing loss 8 2021-02-10 criteria provided, single submitter clinical testing This variant was identified in compound heterozygosity with another variant in the same gene in a male patient with prelingual bilateral severe hearing loss
GeneDx RCV000732326 SCV001779626 pathogenic not provided 2022-08-19 criteria provided, single submitter clinical testing Published functional studies suggest a significant defect in protease activity compared to wild type (Chung et al., 2014); 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: 34416374, 23208854, 21786053, 28246597, 23958653, 17551081, 24526180, 31045651, 31980526, 31589614, 35961784, 35062939, 34599368, 34868270)
Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospital RCV000779355 SCV001792228 pathogenic Autosomal recessive nonsyndromic hearing loss 8 criteria provided, single submitter research in compound heterozygosis with the c.1276G>A variant in three siblings with bilateral non-syndromic sensorineural postlingual progressive hearing loss; 7 normal hearing heterozygous of either variant, 2 normal hearing w/o variants (familial)
Invitae RCV000732326 SCV002120418 pathogenic not provided 2024-01-28 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 306 of the TMPRSS3 protein (p.Ala306Thr). This variant is present in population databases (rs181949335, gnomAD 0.06%). This missense change has been observed in individual(s) with non-syndromic hearing loss (PMID: 17551081, 23208854, 24526180, 28246597, 28695016, 31045651). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Korean and Chinese ancestry (PMID: 24526180, 28695016). ClinVar contains an entry for this variant (Variation ID: 46131). 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 80%. For these reasons, this variant has been classified as Pathogenic.
3billion RCV000779355 SCV002572748 pathogenic Autosomal recessive nonsyndromic hearing loss 8 2022-09-01 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: 0.015%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.85; 3Cnet: 0.83). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000046131). 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: 23958653 , 24526180). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000732326 SCV001952945 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000732326 SCV001974494 pathogenic not provided no assertion criteria provided clinical testing

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