Submissions for variant NM_138691.3(TMC1):c.100C>T (p.Arg34Ter)

gnomAD frequency: 0.00006  dbSNP: rs121908073

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211859	SCV000064814	pathogenic	Rare genetic deafness	2012-03-13	criteria provided, single submitter	clinical testing	The p.Arg34X variant in TMC1 has been reported in more than 23 probands with sen sorineural hearing loss (Kurima 2002, Ben Said 2010, Sirmaci 2009, Kitajiri 2007 , Shafique 2014). Most of these probands, as well as their affected relatives, w ere homozygous for the variant. The p.Arg34X variant has also been identified in 4/15682 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs121908073). Although this variant has been s een in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Animal models in mice have shown that loss of TM C1 function causes an auditory phenotype (Kurima 2002). This nonsense variant le ads to a premature termination codon at position 34, which is predicted to lead to a truncated or absent protein. In summary, the p.Arg34X variant meets our cri teria to be classified as pathogenic for hearing loss in an autosomal recessive manner.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756783	SCV000884693	pathogenic	not provided	2017-07-18	criteria provided, single submitter	clinical testing	The p.Arg34Ter variant is the most frequently reported pathogenic variant of TMC1 and is likely a founder variant in North African and Middle Eastern populations (Kurima 2002, Ben Said 2010, Shafique 2014, and Dallol 2016). The c.100C>T variant creates a premature termination codon in exon 7 and is predicted to result in a truncated or absent protein product. Based on these observations the p.Arg34Ter variant has been classified pathogenic.
GeneDx	RCV000756783	SCV000890354	pathogenic	not provided	2022-03-07	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; This variant is associated with the following publications: (PMID: 25525159, 17877751, 27766948, 24949729, 11850618, 29048421, 20373850, 19187973, 31854501, 31541171, 34426522, 32802042, 32747562, 31589614)
Baylor Genetics	RCV000004319	SCV001522010	pathogenic	Autosomal recessive nonsyndromic hearing loss 7	2020-02-06	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
3billion	RCV000004319	SCV002058633	pathogenic	Autosomal recessive nonsyndromic hearing loss 7	2022-01-03	criteria provided, single submitter	clinical testing	Stop-gained (nonsense): 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 (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000004103, PMID:11850618, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000056, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
King Laboratory, University of Washington	RCV000004319	SCV002059893	pathogenic	Autosomal recessive nonsyndromic hearing loss 7	2020-08-01	criteria provided, single submitter	research	TMC1 c.100C>T, p.R34* is homozygous in 3 Palestinian children with profound pre-lingual hearing loss It was found also in 2 Palestinian children with hearing loss in compound heterozygosity with TMC1 c.1532C>A. The variant is absent from 1300 Palestinian controls and absent from gnomAD v2.1.1.
Invitae	RCV000756783	SCV002218316	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg34*) in the TMC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMC1 are known to be pathogenic (PMID: 11850618, 22105175). This variant is present in population databases (rs121908073, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with autosomal recessive deafness (PMID: 11850618, 17877751, 31854501). ClinVar contains an entry for this variant (Variation ID: 4103). For these reasons, this variant has been classified as Pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003987310	SCV004804963	pathogenic	Autosomal dominant nonsyndromic hearing loss 36	2024-03-17	criteria provided, single submitter	research
OMIM	RCV000004319	SCV000024490	pathogenic	Autosomal recessive nonsyndromic hearing loss 7	2007-12-01	no assertion criteria provided	literature only
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000004319	SCV000223953	pathogenic	Autosomal recessive nonsyndromic hearing loss 7	2014-10-24	no assertion criteria provided	clinical testing
Hereditary Research Laboratory, Bethlehem University	RCV000004319	SCV000538122	pathogenic	Autosomal recessive nonsyndromic hearing loss 7	2016-06-04	no assertion criteria provided	research	FA3 moderate HL at 6y; FA4 profound at 18m
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000004319	SCV000902388	pathogenic	Autosomal recessive nonsyndromic hearing loss 7	2019-02-26	no assertion criteria provided	case-control
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291357	SCV001479831	likely pathogenic	Hearing loss, autosomal recessive		no assertion criteria provided	research
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000004319	SCV003927953	pathogenic	Autosomal recessive nonsyndromic hearing loss 7	2023-04-01	no assertion criteria provided	clinical testing