Submissions for variant NM_001256317.3(TMPRSS3):c.208del (p.His70fs)

dbSNP: rs727503493

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152065	SCV000200697	pathogenic	Rare genetic deafness	2024-04-08	criteria provided, single submitter	clinical testing	The p.His70ThrfsX19 variant in TMPRSS3 has been reported in the homozygous or compound heterozygous state in more than 10 individuals with nonsyndromic hearing loss and segregated with disease in more than 10 affected relatives from over 5 families (Wattenhofer 2002 PMID: 11907649, Ahmed 2004 PMID: 15447792, Kecmanović 2008 PMID: 19170735, Weegerink 2011 PMID: 21786053, Lee 2012 PMID: 21534946, Battelino 2016 PMID: 26036852, LMM data). It has been identified in 0.1% (1202/1180022) of European chromosomes, including 1 homozygote by gnomAD (http://gnomAD.broadinstitute.org, v4.0.0); however, this frequency is low enough to be consistent with a recessive carrier frequency for hearing loss. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 70 and leads to a premature stop codon 19 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the TMPRSS3 gene is an established disease mechanism in autosomal recessive nonsyndromic hearing loss. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PP1_Strong, PM2_Supporting.
Illumina Laboratory Services, Illumina	RCV000371920	SCV000436178	pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2017-04-27	criteria provided, single submitter	clinical testing	The TMPRSS3 c.208delC (p.His70ThrfsTer19) variant has been reported in at least six studies and is found in a total of at least 27 individuals with nonsyndromic hearing loss, including 24 in a homozygous state and three in a compound heterozygous state (Wattenhofer et al. 2002; Ahmed et al. 2004; Kecmanovic et al. 2009; Weegerink et al. 2011; Lee et al. 2012; Battelino et al. 2015). The variant segregated with disease in at least three unrelated families. The p.His70ThrfsTer19 variant was absent from 700 control alleles but is reported at a frequency of 0.00074 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.His70ThrfsTer19 variant results in a frameshift, and is predicted to result in premature termination of the protein. Due to the potential impact of frameshift variants and the supporting evidence from the literature, the p.His70ThrfsTer19 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	RCV000412773	SCV000491099	pathogenic	not provided	2022-04-25	criteria provided, single submitter	clinical testing	Frameshift 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; This variant is associated with the following publications: (PMID: 15447792, 27573290, 19170735, 21534946, 11907649, 21786053, 26036852, 28566687, 29293505, 31270413, 31980526, 31412945, 34171171, 31589614, 32853555, 32860223)
Ambry Genetics	RCV000623444	SCV000742260	pathogenic	Inborn genetic diseases	2023-12-19	criteria provided, single submitter	clinical testing	The c.208delC (p.H70Tfs*19) alteration, located in exon 4 (coding exon 3) of the TMPRSS3 gene, consists of a deletion of one nucleotide at position 208, causing a translational frameshift with a predicted alternate stop codon after 19 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of 0.048% (136/282628) total alleles studied. The highest observed frequency was 0.097% (10/10364) of Ashkenazi Jewish alleles. This alteration has been reported homozygous or compound heterozygous with a second TMPRSS3 alteration in multiple patients with features consistent with TMPRSS3-related deafness (Wattenhofer, 2002; Battelino, 2016; Lechowicz, 2017; Likar, 2018; Roman, 2020; Moon, 2021). Based on the available evidence, this alteration is classified as pathogenic.
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000371920	SCV001251529	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 8		criteria provided, single submitter	research	TMPRSS3 c.208delC (p.H70Tfs) is a frameshift variant that is predicted to result in a nonfunctional protein. This variant has been reported previously in the homozygous or compound heterozygous state in multiple individuals with autosomal recessive nonsyndromic hearing loss (PMID: 11907649, 21534946, 21786053; 26036852).
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000371920	SCV001366892	pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2019-08-26	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000412773	SCV001449025	pathogenic	not provided	2019-07-03	criteria provided, single submitter	clinical testing
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375379	SCV001571764	likely pathogenic	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PVS1_Strong, PM2_Supporting, PM5_Moderate
Invitae	RCV000412773	SCV002174397	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.His70Thrfs*19) 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 (rs727503493, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive deafness (PMID: 11907649, 28566687, 29293505). This variant is also known as 207delC. ClinVar contains an entry for this variant (Variation ID: 165492). For these reasons, this variant has been classified as Pathogenic.
The Shared Resource Centre "Genome", Research Centre for Medical Genetics	RCV000371920	SCV002756436	pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2022-11-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000371920	SCV002776345	pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2021-09-17	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV003993831	SCV004812871	pathogenic	Nonsyndromic genetic hearing loss	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change in TMPRSS3 is a frameshift variant predicted to cause a premature stop codon, p.(His70Thrfs*19), in biologically relevant exon 4/13 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.1% (1,202/1,180,022 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: 21534946, 26036852). 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: 29293505, 30242206, 26036852, 28566687). 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, PVS1
CeGaT Center for Human Genetics Tuebingen	RCV000412773	SCV005041837	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	TMPRSS3: PM3:Very Strong, PVS1, PP1:Strong, PM2
OMIM	RCV000371920	SCV000044740	pathogenic	Autosomal recessive nonsyndromic hearing loss 8	2002-02-01	no assertion criteria provided	literature only
Genomics England Pilot Project, Genomics England	RCV000371920	SCV001760470	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 8		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000412773	SCV001952661	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000412773	SCV001965067	pathogenic	not provided		no assertion criteria provided	clinical testing