ClinVar Miner

Submissions for variant NM_001256317.3(TMPRSS3):c.413C>A (p.Ala138Glu) (rs147231991)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000039356 SCV000063040 pathogenic Rare genetic deafness 2016-03-31 criteria provided, single submitter clinical testing The p.Ala138Glu variant in TMPRSS3 has been reported in the homozygous or compou nd heterozygous state in more than 10 probands with nonsyndromic hearing loss an d has segregated in 5 affected family members (Eppsteiner 2012, Hutchin 2005, We egerink 2011, LMM data). This variant has been identified in 0.1% (82/67696) Eur opean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadin stitute.org; rs147231991); however, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conserva tion analysis suggest that this variant may impact the protein. In summary, the p.Ala138Glu variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss based on the previous reports of biallelic states in affected individuals and segregations with hearing loss. ACMG/AMP Crit eria applied: PM3_VeryStrong, PP1_Strong, PP3.
Illumina Clinical Services Laboratory,Illumina RCV000454169 SCV000436174 pathogenic Deafness, autosomal recessive 8 2018-03-20 criteria provided, single submitter clinical testing The TMPRSS3 c.413C>A (p.Ala138Glu) variant was identified in a total of 14 individuals with an autosomal recessive form of hearing loss, including in two homozygotes from one family and in a total of 12 compound heterozygotes from seven unrelated families. The variant was also found in a heterozygous state in three unaffected parents (Hutchin et al. 2005; Weegerink et al. 2011; Eppsteiner et al. 2012). The p.Ala138Glu variant was absent from 165 controls, but is reported at a frequency of 0.00121 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Ala138Glu variant is classified as pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV000413170 SCV000491297 pathogenic not provided 2021-05-27 criteria provided, single submitter clinical testing 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: 25262649, 31152317, 16283880, 21786053, 22975204, 28566687, 29431110, 31053783, 28695016, 31980526, 31589614)
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000454169 SCV000538067 likely pathogenic Deafness, autosomal recessive 8 2016-01-27 criteria provided, single submitter clinical testing The c. 413C>A (p. Ala138Glu) missense variant in the TMPRSS3 gene has previously been reported as homozygous in two siblings who were affected with autosomal recessive non-syndromic hearing loss [Hutchin T et al., (2005)]. Additionally, this variant has been seen in trans with a known pathogenic variant (Ala306Thr) and also co-segregated with disease in multiple affected family members in several families [Weegerink NJ et al., (2011)]. The prevalence of this variant in affected individuals is significantly increased compared with the prevalence in controls. The frequency of this variant in the three control population databases (Exome Sequencing Project [ESP], 1000 Genomes, and ExAC) is lower than the disease-allele frequency, and no homozygotes for this variant are observed in the population databases. Several computational algorithms predict a deleterious effect of this variant on the protein. Finally, reputable clinical sources have classified this variant as either Likely Pathogenic or Pathogenic. Therefore, this collective evidence supports the Likely Pathogenic classification of the c.413C>A (p. Ala138Glu) variant in the TMPRSS3 gene for Non-syndromic hearing loss (DFNB8/10). We have confirmed this finding in our laboratory using Sanger sequencing.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000413170 SCV001246791 pathogenic not provided 2020-03-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000454169 SCV001338634 pathogenic Deafness, autosomal recessive 8 2020-04-07 criteria provided, single submitter clinical testing Variant summary: TMPRSS3 c.413C>A (p.Ala138Glu) results in a non-conservative amino acid change located in the SRCR domain (IPR001190) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00092 in 251450 control chromosomes. c.413C>A has been reported in the literature in multiple individuals affected with Deafness, autosomal recessive 8 (examples- Hutchin_2005, Weegerink_2011, Eppsteiner_2012), and has been shown to segregate with disease in affected family members. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other ClinVar submitters have cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center RCV001375181 SCV001571787 likely pathogenic Hearing impairment 2021-04-12 criteria provided, single submitter clinical testing PS1_Strong, PM2_Moderate, PP3_Supporting
Genomics England Pilot Project,Genomics England RCV000454169 SCV001760469 likely pathogenic Deafness, autosomal recessive 8 criteria provided, single submitter clinical testing
Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospital RCV000454169 SCV001792230 pathogenic Deafness, autosomal recessive 8 criteria provided, single submitter research in compound heterozygosis with the c.346G>A variant in a subject with non-syndromic sensorineural postlingual progressive hearing loss (sporadic)
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000413170 SCV001905630 pathogenic not provided 2021-09-15 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000454169 SCV001950041 likely pathogenic Deafness, autosomal recessive 8 2021-08-11 criteria provided, single submitter clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000413170 SCV001979666 likely pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000413170 SCV001980332 pathogenic not provided no assertion criteria provided clinical testing

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