ClinVar Miner

Submissions for variant NM_138691.3(TMC1):c.741+1G>A

dbSNP: rs1588067173
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000825547 SCV000966864 likely pathogenic Rare genetic deafness 2018-10-10 criteria provided, single submitter clinical testing The c.741+1G>A variant in TMC1 has been previously reported in at least 1 indivi dual with hearing loss (Sloan-Heggen 2015), and was absent from large population studies. This variant occurs in the canonical splice site (+/- 1,2) of the spli ce consensus sequence and is predicted to cause altered splicing leading to an a bnormal or absent protein. Loss of function of the TMC1 gene is an established d isease mechanism in autosomal recessive hearing loss. In summary, although addit ional studies are required to fully establish its clinical significance, this va riant meets criteria to be classified as likely pathogenic for autosomal recessi ve sensorineural hearing loss. ACMG/AMP Criteria applied: PVS1_Strong, PM2.
Labcorp Genetics (formerly Invitae), Labcorp RCV003558604 SCV004294318 pathogenic not provided 2023-03-08 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 666986). Disruption of this splice site has been observed in individual(s) with autosomal recessive deafness (PMID: 26445815; Inivitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 12 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).

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