Submissions for variant NM_138691.3(TMC1):c.236+1G>A

gnomAD frequency: 0.00003  dbSNP: rs775428246

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000608719	SCV000711267	pathogenic	Rare genetic deafness	2016-05-27	criteria provided, single submitter	clinical testing	The c.236+1G>A variant in TMC1 has been reported in 2 homozygous individuals wit h autosomal recessive nonsyndromic sensorineural hearing loss and segregated wit h hearing loss in 4 affected relatives from those 2 families (Hilgert 2008, Hild ebrand 2010). Another variant at the same position c.236+1G>C has also been repo rted as pathogenic in the literature (Yang 2013). This variant has been identifi ed in 1/42270 European chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs775428246). Although this variant has been seen in the general population, its frequency is low enough to be consistent wi th a recessive carrier frequency. This variant occurs in the invariant region (+ /- 1/2) of the splice consensus sequence and is predicted to cause altered splic ing leading to an abnormal or absent protein. Loss of function of the TMC1 gene is an established disease mechanism in autosomal recessive nonsyndromic sensorin eural hearing loss. In summary, this variant meets our criteria to be classified as pathogenic for autosomal recessive nonsyndromic sensorineural hearing loss.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000626300	SCV000746961	pathogenic	Autosomal dominant nonsyndromic hearing loss 36	2020-05-03	criteria provided, single submitter	clinical testing
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV000770875	SCV000924178	pathogenic	Autosomal recessive nonsyndromic hearing loss 7		criteria provided, single submitter	research
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814196	SCV001755265	pathogenic	Ear malformation	2021-07-10	criteria provided, single submitter	clinical testing
GeneDx	RCV002282262	SCV002571669	pathogenic	not provided	2022-09-10	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 31541171, 18616530, 31028865, 21250555, 31589614, 33205915, 23767834, 27344577)
Invitae	RCV002282262	SCV003441344	pathogenic	not provided	2023-12-03	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 7 of the TMC1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TMC1 are known to be pathogenic (PMID: 11850618, 22105175). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individuals with autosomal recessive deafness (PMID: 18616530, 23767834, 31028865, 31541171). ClinVar contains an entry for this variant (Variation ID: 504715). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000770875	SCV000902389	pathogenic	Autosomal recessive nonsyndromic hearing loss 7	2019-02-26	no assertion criteria provided	case-control
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000770875	SCV004041741	pathogenic	Autosomal recessive nonsyndromic hearing loss 7	2023-10-09	no assertion criteria provided	clinical testing