ClinVar Miner

Submissions for variant NM_001256317.3(TMPRSS3):c.727G>A (p.Gly243Arg)

gnomAD frequency: 0.00001  dbSNP: rs372526764
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Total submissions: 5
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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 RCV000155297 SCV000204983 likely pathogenic Rare genetic deafness 2014-12-06 criteria provided, single submitter clinical testing The p.Gly243Arg variant in TMPRSS3 has been reported in one Indian individual wi th hearing loss (Ganapathy 2014). The variant was detected in the homozygous sta te in the proband and in two affected siblings, and the parents who were heteroz ygous carriers were unaffected (Ganapathy 2014). In addition the variant has bee n previously detected in the homozygous state by our laboratory in one individua l with profound sensorineural hearing loss (this individual's son). The p.Gly243 Arg variant has been identified in 1/8600 European American chromosomes by the N HLBI Exome Sequencing Project and in 3/16618 South Asian chromosomes by the Exom e Aggregation Consortium (http://evs.gs.washington.edu/EVS/; http://exac.broadin stitute.org; dbSNP rs372526764). Although this variant has been seen in the gene ral population, its frequency is low enough to be consistent with a recessive ca rrier frequency. Computational prediction tools and conservation analyses sugges t that the p.Gly243Arg variant may impact the protein, though this information i s not predictive enough to determine pathogenicity. In summary, although additio nal studies are required to fully establish its clinical significance, this vari ant is likely pathogenic.
GenePathDx, GenePath diagnostics RCV000487440 SCV000574531 likely pathogenic Autosomal recessive nonsyndromic hearing loss 8 2016-05-01 criteria provided, single submitter clinical testing 12 years old child with deafness and a history of parental consanguinity. Next generation DNA sequencing of peripheral blood sample has revealed presence of a homozygous variant c.727 G>A in exon 8 of TMPRSS3 gene. This variant was predicted to be likely pathogenic based on available evidences in the databases and in silico mutation prediction methods.
CeGaT Center for Human Genetics Tuebingen RCV002292477 SCV002585902 likely pathogenic not provided 2022-09-01 criteria provided, single submitter clinical testing TMPRSS3: PM2, PM3, PP1:Moderate
PreventionGenetics, part of Exact Sciences RCV003407579 SCV004115589 likely pathogenic TMPRSS3-related disorder 2023-02-23 criteria provided, single submitter clinical testing The TMPRSS3 c.727G>A variant is predicted to result in the amino acid substitution p.Gly243Arg. This variant is located in the highly conserved catalytic serine protease domain, and was reported in the homozygous state in three siblings with autosomal recessive non-syndromic deafness (Ganapathy et al. 2014. PubMed ID: 24416283). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/21-43803197-C-T). This variant is interpreted as likely pathogenic.
Invitae RCV002292477 SCV004297396 pathogenic not provided 2023-09-19 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 243 of the TMPRSS3 protein (p.Gly243Arg). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 178549). This missense change has been observed in individual(s) with deafness (PMID: 24416283). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs372526764, gnomAD 0.01%).

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