Submissions for variant NM_001256317.3(TMPRSS3):c.46C>T (p.Arg16Ter)

gnomAD frequency: 0.00001  dbSNP: rs976363536

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
3billion	RCV002283552	SCV002572825	pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV001210028 / PMID: 27344577). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
The Shared Resource Centre "Genome", Research Centre for Medical Genetics	RCV002283552	SCV002756438	pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2022-11-10	criteria provided, single submitter	clinical testing
GeneDx	RCV001579830	SCV003929964	pathogenic	not provided	2022-12-03	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22133722, 30245029, 27344577)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001579830	SCV004297404	pathogenic	not provided	2023-10-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg16*) in the TMPRSS3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMPRSS3 are known to be pathogenic (PMID: 16021470, 26969326). This variant is present in population databases (no rsID available, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with nonsyndromic deafness (PMID: 27344577, 28984810). ClinVar contains an entry for this variant (Variation ID: 1210028). For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001579830	SCV005198808	likely pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001579830	SCV001808655	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001579830	SCV001954571	pathogenic	not provided		no assertion criteria provided	clinical testing