ClinVar Miner

Submissions for variant NM_001256317.3(TMPRSS3):c.646C>T (p.Arg216Cys)

gnomAD frequency: 0.00002  dbSNP: rs145913750
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center of Genomic medicine, Geneva, University Hospital of Geneva RCV001806227 SCV001745848 pathogenic Autosomal recessive nonsyndromic hearing loss 8 2020-10-07 criteria provided, single submitter clinical testing This variant was identified in compound heterozygosity with another variant in the same gene in a female patient with congenital bilateral severe hearing loss
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001806227 SCV004029696 pathogenic Autosomal recessive nonsyndromic hearing loss 8 2023-07-28 criteria provided, single submitter clinical testing Variant summary: TMPRSS3 c.646C>T (p.Arg216Cys) results in a non-conservative amino acid change located in the Serine proteases, trypsin domain (IPR001254) of the encoded protein sequence. 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 2.4e-05 in 251338 control chromosomes (gnomAD). c.646C>T has been reported in the literature in multiple individuals affected with Deafness (examples: Elbracht_2007, Boudewyns_2018, and, Van Heurck_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 29889784, 17551081, 34440452). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV003558834 SCV004297398 pathogenic not provided 2024-01-21 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 216 of the TMPRSS3 protein (p.Arg216Cys). This variant is present in population databases (rs145913750, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive nonsyndromic deafness (PMID: 17551081). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1175710). 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%. This variant disrupts the p.Arg216 amino acid residue in TMPRSS3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26445815). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV003558834 SCV004700145 pathogenic not provided 2024-05-01 criteria provided, single submitter clinical testing TMPRSS3: PM3:Very Strong, PP1:Strong, PM2, PM5
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV001806227 SCV005086100 pathogenic Autosomal recessive nonsyndromic hearing loss 8 2023-12-21 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness, autosomal recessive 8/10 (MIM#601072). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (6 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v3) (highest allele count: 3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. ClinVar contains two likely pathogenic entries for p.(Arg216His), and p.(Arg216Leu) has been reported in two homozygous brothers with autosomal recessive post-lingual hearing loss (PMID: 16021470). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by two clinical laboratories in ClinVar, and has been reported in multiple unrelated compound heterozygous individual with hearing loss (PMID: 17551081, 29889784, 34440452, 22975204). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Laboratory of Human Genetics, Universidade de São Paulo RCV004719042 SCV005324787 pathogenic Hearing loss, autosomal recessive 2024-05-01 criteria provided, single submitter research The TMPRSS3:c.646C>T:p.Arg216Cys variant has extremely low frequency in gnomAD population databases (PM2), localized in a mutational hotspot (PM1). Different amino acid change as a known pathogenic variant (PM5), computational prediction tools unanimously support a deleterious effect on the gene (PP3). It is in homozygosis in two affected siblings born from consanguineous couple, thus segregates with hearing loss (PM3, PP1) .

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