ClinVar Miner

Submissions for variant NM_001256317.3(TMPRSS3):c.1340T>C (p.Met447Thr) (rs201018751)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000039341 SCV000063025 likely pathogenic Rare genetic deafness 2015-10-24 criteria provided, single submitter clinical testing The p.Met448Thr variant in TMPRSS3 has been identified by our laboratory in 1 Ca ucasian individual with congenital sensorineural hearing loss who had two clinic ally significant variants in another gene that likely explained the hearing loss (LMM unpublished data). This variant has also been identified in 2/66540 Europe an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs201018751); however its frequency is low enough to be consiste nt with a recessive carrier frequency. Computational prediction tools and conser vation analysis do not provide strong support for or against an impact to the pr otein. The presence of this variant in trans with a second variant in TMPRSS3 an d the segregation of the two variants in an affected sibling with hearing loss i ncreases the likelihood that the p.Met448Thr variant is pathogenic. In summary, although additional studies are required to fully establish its clinical signifi cance, this variant is likely pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV001140597 SCV001300869 uncertain significance Deafness, autosomal recessive 8 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV001559611 SCV001781877 likely pathogenic not provided 2020-10-02 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32860223, 31412945, 28566687)
Institute of Human Genetics, University of Leipzig Medical Center RCV001140597 SCV001950040 uncertain significance Deafness, autosomal recessive 8 2021-08-11 criteria provided, single submitter clinical testing

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