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

gnomAD frequency: 0.00105  dbSNP: rs56264519

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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, http://gnomad.broadinstitute.org); 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.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000039339	SCV000223954	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2015-04-01	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000428693	SCV000225700	likely pathogenic	not provided	2015-03-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000428693	SCV000521273	pathogenic	not provided	2023-01-04	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: 21786053, 11907649, 24526180, 21534946, 28263784, 30487145, 31412945, 34426522, 31980526, 30242206, 33297549, 31589614, 34652575, 32860223, 34599368, 34997062, 34171171, 28566687, Ozieblo_2022_IJMS, 29196752, 12920079, 33879512, 35961784, 34868270, 35682719)
Genetic Services Laboratory, University of Chicago	RCV000039339	SCV000597505	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2017-03-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000039339	SCV000611244	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2021-09-29	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	Autosomal recessive nonsyndromic hearing loss 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 genetic hearing loss	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.
Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospital	RCV000039339	SCV001792227	pathogenic	Autosomal recessive nonsyndromic hearing loss 8		criteria provided, single submitter	research	in compound heterozygosis with the c.916G>A variant in three siblings with bilateral non-syndromic sensorineural postlingual progressive hearing loss; 7 normal hearing heterozygous of either variant, 2 normal hearing w/o variants (familial)
Revvity Omics, Revvity	RCV000039339	SCV002020240	pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2022-07-01	criteria provided, single submitter	clinical testing
Invitae	RCV000428693	SCV002197852	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 426 of the TMPRSS3 protein (p.Ala426Thr). This variant is present in population databases (rs56264519, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with nonsyndromic hearing loss (PMID: 21786053, 28566687, 29196752, 30242206). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Ala425Thr. ClinVar contains an entry for this variant (Variation ID: 46102). 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%. Experimental studies have shown that this missense change affects TMPRSS3 function (PMID: 12920079). For these reasons, this variant has been classified as Pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV000039339	SCV002556741	pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2022-07-01	criteria provided, single submitter	clinical testing	The TMPRSS3 c.1273G>A variant is classified as PATHOGENIC (PS3, PS4, PM3, PP1_moderate) The TMPRSS3 c.1273G>A variant is a single nucleotide change in exon 12/13 of the TMPRSS3 gene, which is predicted to change the amino acid alanine at position 425 in the protein to threonine. The variant has been reported in multiple individuals with a clinical presentation of Deafness, autosomal recessive 8/10 (MIM:601072) (PMID:21786053; PMID:31412945; PMID:28566687) (PS4). Published studies have shown this variant to co-segregate with disease in multiple families (PMID:21786053; PMID:31412945; PMID:28566687) (PP1_moderate). In vitro functional studies have shown this variant leads to reduced proteolytic activity of ~24% compared with WT (PMID:12920079) (PS3). This variant has been reported in dbSNP (rs56264519) and has been reported in population databases (163/152110, 1 homozygote). This variant has been reported in ClinVar as Pathogenic by other clinical laboratories (Variation ID: 46102) and as damaging for nonsyndromic hearing loss in the disease database HGMD (CM116227).
CeGaT Center for Human Genetics Tuebingen	RCV000428693	SCV004153707	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	TMPRSS3: PM3:Very Strong, PP1:Strong, PM2:Supporting, PS3:Supporting
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000039339	SCV004171709	pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2023-12-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000428693	SCV004225756	pathogenic	not provided	2022-06-07	criteria provided, single submitter	clinical testing	PP1_strong, PM3_very_strong, PS3_moderate
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.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000428693	SCV001957386	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000428693	SCV001970140	likely pathogenic	not provided		no assertion criteria provided	clinical testing