ClinVar Miner

Submissions for variant NM_138691.2(TMC1):c.100C>T (p.Arg34Ter) (rs121908073)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 ://; 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.
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000004319 SCV000223953 pathogenic Deafness, autosomal recessive 7 2014-10-24 criteria provided, single submitter clinical testing
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 2018-12-11 criteria provided, single submitter clinical testing The R34X pathogenic variant in the TMC1 gene has been reported previously in the homozygous state in multiple individuals of middle Eastern descent with autosomal recessive nonsyndromic hearing loss, and appears to represent a founder mutation (Kurima et al., 2002; Sirmaci et al., 2009; Ben Said et al., 2010; Shafique et al., 2014; Dallol et al., 2016; Almontashiri et al., 2018). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R34X variant is observed in 9/30,676 (0.029%) alleles from individuals of South Asian background and 16/244,438 (0.0065%) total alleles in large population cohorts, with no homozygous individuals observed (Lek et al., 2016). We interpret R34X as a pathogenic variant.
OMIM RCV000004319 SCV000024490 pathogenic Deafness, autosomal recessive 7 2007-12-01 no assertion criteria provided literature only
Hereditary Research Laboratory,Bethlehem University RCV000004319 SCV000538122 pathogenic Deafness, autosomal recessive 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 Deafness, autosomal recessive 7 2019-02-26 no assertion criteria provided case-control

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