ClinVar Miner

Submissions for variant NM_001256317.3(TMPRSS3):c.1273G>A (p.Ala425Thr) (rs56264519)

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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, Partners HealthCare Personalized Medicine RCV000211742 SCV000063023 pathogenic Rare genetic deafness 2018-11-12 criteria provided, single submitter clinical testing The p.Ala426Thr variant in TMPRSS3 has been reported in >10 individuals with hea ring loss, at least 4 of whom harbored a second pathogenic variant in TMPRSS3 (2 compound heterozygous occurences and 2 co-occurences with phase unknown; Watten hofer 2002, Weegerink 2011, Baux 2017, Lechowicz 2017, LMM data). Furthermore, t he p.Ala426Thr variant segregated with disease in 5 affected relatives from 2 fa milies (Weegerink 2011, LMM data). This variant has also been identified in 0.15 % (187/129114) of European chromosomes by the Genome Aggregation Database (gnomA D,; however, this frequency is low enough to b e consistent with a recessive carrier frequency. In vitro functional studies sup port an impact on protein function (Lee 2003). Finally, this variant has been re ported as Likely Pathogenic in ClinVar (Variation ID 46102). In summary, the p.A la426Thr variant meets criteria to be classified as pathogenic for hearing loss in an autosomal recessive manner based upon biallelic case observations, segrega tion studies and functional evidence. ACMG/AMP Criteria applied: PM3_Strong, PP1 _Strong, PP3, PS3_Supporting.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000428693 SCV000225700 likely pathogenic not provided 2015-03-31 criteria provided, single submitter clinical testing
GeneDx RCV000428693 SCV000521273 likely pathogenic not provided 2021-04-30 criteria provided, single submitter clinical testing Published functional studies suggest a damaging effect as the variant showed significantly diminished colony formation in a protease assay compared to wild-type (Lee et al., 2003); 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: 33297549, 30242206, 31980526, 31412945, 12920079, 30487145, 28566687, 28263784, 21534946, 21786053, 24526180, 11907649)
Genetic Services Laboratory, University of Chicago RCV000039339 SCV000597505 likely pathogenic Deafness, autosomal recessive 8 2017-03-22 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000428693 SCV000611244 likely pathogenic not provided 2017-05-18 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000428693 SCV001474923 likely pathogenic not provided 2020-08-07 criteria provided, single submitter clinical testing The best available variant frequency is consistent with disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. Strong co-segregation with disease in affected individuals from a single family.
Baylor Genetics RCV000039339 SCV001524839 pathogenic Deafness, autosomal recessive 8 2019-11-25 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
INGEBI, INGEBI / CONICET RCV001544534 SCV001763580 pathogenic Nonsyndromic hearing loss and deafness 2021-07-15 criteria provided, single submitter clinical testing Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria:The filtering allele frequency of c.1276G>A variant (p.A426T) in TMPRSS3 gene is 0.1% (187/129114 with 95% CI) in european non-finnish ethnic group obtanied from gnomAD population database, meeting BS1_Sup. This variant has been found in trans with 4 pathogenic/likely pathogenic variants in hearing impairment patients applying for PM3_VS (PMID: 21786053, 28566687, 29196752 and this report). There is one familial case with four sibling that showed high frequency hearing impairment with childhood onset and eight siblings with normal hearing. All the affected members had the A426T variant in trans with a pathogenic variant in TMPRSS3 gene while all the unaffected siblings carried only one variant or were wild type, applying to PP1_Strong (PMID: 21786053). A yeast based protease assay demonstrated that A426T mutatn possesed a significantly disminished protelotytic activity, PMID:12920079, PS3_Sup. Considering: BS1_Sup, PM3_VS, PP1_S and PS3_Sup, the c.1276G>A variant is classified as Pathogenic for autosomal recessive non-syndromic hearing loss.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000039339 SCV000223954 likely pathogenic Deafness, autosomal recessive 8 2015-04-01 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000428693 SCV001548815 pathogenic not provided no assertion criteria provided clinical testing The TMPRSS3 p.A426T variant has been reported in multiple cases of hearing loss and was found to segregate with disease in five affected individuals from two families who were compound heterozygous for this variant and another pathogenic variant (Weegerink_2011_PMID:21786053, Oldak_2019_PMID:31412945; Lechowicz_2017_PMID:28566687). The variant was identified in dbSNP (ID: rs56264519), LOVD 3.0 and ClinVar (classified as pathogenic by Laboratory for Molecular Medicine and as likely pathogenic by Fulgent Genetics, GeneDx, Knight Diagnostic Laboratories, EGL Genetic Diagnostics and Genetics Services Laboratory, University of Chicago). The variant was identified in control databases in 268 of 282764 chromosomes at a frequency of 0.0009478 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 187 of 129114 chromosomes (freq: 0.001448), Latino in 50 of 35432 chromosomes (freq: 0.001411), Other in 9 of 7220 chromosomes (freq: 0.001247), Ashkenazi Jewish in 5 of 10366 chromosomes (freq: 0.000482), African in 9 of 24950 chromosomes (freq: 0.000361), South Asian in 5 of 30616 chromosomes (freq: 0.000163) and European (Finnish) in 3 of 25116 chromosomes (freq: 0.000119), but was not observed in the East Asian population. The p.A426 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Functional analysis in yeast demonstrated that the p.A426T variant caused significantly reduced protein activity (Lee_2003_PMID: 12920079). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Human Genetics - Radboudumc,Radboudumc RCV000428693 SCV001957386 likely pathogenic not provided no assertion criteria provided clinical testing

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