Submissions for variant NM_001256317.3(TMPRSS3):c.239G>A (p.Arg80His)

gnomAD frequency: 0.00013  dbSNP: rs146159479

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156655	SCV000206376	likely benign	not specified	2014-07-16	criteria provided, single submitter	clinical testing	p.Arg80His in exon 4 of TMPRSS3: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, 5 mammals (mouse, rat, golden hamster, chinese hamster, and prairie vole) have a histidine (His) at this position despite high nearby amino acid conservat ion. In addition, computational prediction tools do not suggest a high likelihoo d of impact to the protein. This variant has been identified in 0.12% (11/8650) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs146159479).
Illumina Laboratory Services, Illumina	RCV000317265	SCV000436177	uncertain significance	Autosomal recessive nonsyndromic hearing loss 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850168	SCV002167948	uncertain significance	not provided	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 80 of the TMPRSS3 protein (p.Arg80His). This variant is present in population databases (rs146159479, gnomAD 0.4%). This missense change has been observed in individual(s) with non syndromic deafness (PMID: 26346818, 32235586). ClinVar contains an entry for this variant (Variation ID: 179855). 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 not expected to disrupt TMPRSS3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001850168	SCV003935712	uncertain significance	not provided	2024-04-26	criteria provided, single submitter	clinical testing	Observed as a heterozygous variant with no second TMPRSS3 variant identified in a patient with hearing loss in the published literature (PMID: 32235586); Published functional studies demonstrate a damaging effect due to reduced proteolytic activity (PMID: 32235586); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 26346818, 34868270, 32235586, 37331337)