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

gnomAD frequency: 0.00146  dbSNP: rs147231991

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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 Laboratory Services, Illumina	RCV000454169	SCV000436174	pathogenic	Autosomal recessive nonsyndromic hearing loss 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	2023-09-29	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, 31589614, 36147510, 34868270, 34599368, 34758253, 31980526, 35580552, 35052694)
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000454169	SCV000538067	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 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 Center for Human Genetics Tuebingen	RCV000413170	SCV001246791	pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	TMPRSS3: PM3:Very Strong, PM2, PP1, BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000454169	SCV001338634	pathogenic	Autosomal recessive nonsyndromic hearing loss 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
Kariminejad - Najmabadi Pathology & Genetics Center	RCV000413170	SCV001755199	likely pathogenic	not provided	2021-07-10	criteria provided, single submitter	clinical testing
Genomics England Pilot Project, Genomics England	RCV000454169	SCV001760469	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 8		criteria provided, single submitter	clinical testing
Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospital	RCV000454169	SCV001792230	pathogenic	Autosomal recessive nonsyndromic hearing loss 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	Autosomal recessive nonsyndromic hearing loss 8	2021-08-11	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000454169	SCV002020239	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2023-12-01	criteria provided, single submitter	clinical testing
Invitae	RCV000413170	SCV002144379	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 138 of the TMPRSS3 protein (p.Ala138Glu). This variant is present in population databases (rs147231991, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with deafness (PMID: 16283880, 21786053, 22975204, 28566687, 29431110, 30242206, 31152317). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as p.A11E . ClinVar contains an entry for this variant (Variation ID: 46119). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TMPRSS3 protein function. For these reasons, this variant has been classified as Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000413170	SCV002502428	likely pathogenic	not provided	2021-10-10	criteria provided, single submitter	clinical testing
Genetics Laboratory, Department of Biology, Semnan University	RCV000454169	SCV002569141	pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2018-08-01	criteria provided, single submitter	case-control	The identified mutation leads to the substitution of Alanine 138 to Glutamic acid (A138E) in the TMPRSS3 protein. Hence, this substitution alters the amino acid sequence and leads to abnormal protein function.
MGZ Medical Genetics Center	RCV000454169	SCV002581717	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2022-08-04	criteria provided, single submitter	clinical testing
The Shared Resource Centre "Genome", Research Centre for Medical Genetics	RCV000454169	SCV002756434	pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2022-11-10	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000454169	SCV002767250	pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2022-02-02	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 autosomal recessive deafness 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 alanine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (277 heterozygotes, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (highest allele count: p.(Ala138Thr) - v2: 165 heterozygotes, 0 homozygotes; v3: 78 heterozygotes, 1 homozygote). (I) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (I) 0600 - Variant is located in the annotated scavenger receptor cysteine-rich domain (NCBI, PDB). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple unrelated individuals with hearing loss (PMID: 16283880, 21786053, 22975204, 30242206), and as pathogenic in ClinVar and the Deafness Variation Database. (SP) 0901 - This variant has strong evidence for segregation with disease. This variant segregated with disease in at least two families with autosomal recessive non-syndromic hearing impairment (PMID: 21786053). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV000454169	SCV002785492	pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2021-07-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000454169	SCV004183412	pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2023-09-29	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000413170	SCV004225757	pathogenic	not provided	2022-05-31	criteria provided, single submitter	clinical testing	PP1_strong, PM3_very_strong
Molecular Genetics, Royal Melbourne Hospital	RCV003993760	SCV004812521	pathogenic	Nonsyndromic genetic hearing loss	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change in TMPRSS3 is predicted to replace alanine with glutamic acid at codon 138, p.(Ala138Glu). The alanine residue is moderately conserved (100 vertebrates, Multiz Alignments), and is located in the scavenger receptor cysteine-rich (SRCR) domain. There is a large physicochemical difference between alanine and glutamic acid. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.2% (2,942/1,180,048 alleles) in the European (non-Finnish) population. The variant has been reported to segregate with hearing loss in affected family members from two unrelated families (PMID: 21786053). This variant has been detected in multiple individuals with hearing loss. Of those individuals, at least two individuals were homozygous while the majority of the reported individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (PMID: 37811145, 37713394, 30242206, 22975204, 21786053). Computational evidence is uninformative for the missense substitution (REVEL = 0.595). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1_Strong
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	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