ClinVar Genomic variation as it relates to human health

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.

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)

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.

The NM_138691.2:c.[236+1G>A] variant is a null variant in a gene where loss of function is a known mechanism of disease (PVS1), Extremely low frequency in gnomAD population databases (PM2), For recessive disorders, detected in trans with a pathogenic variant, or in a homozygous or compound heterozygous state in affected cases (PM3), Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1), reported in ClinVar in affected individuals (PP5), Here it was found in trans with c.1094G>A in two affected siblings, born from unaffected unrelated couple.