ClinVar Genomic variation as it relates to human health

Variant summary: SLC26A4 c.165-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.8e-05 in 251488 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (4.8e-05 vs 0.0035), allowing no conclusion about variant significance. c.165-1G>A has been reported in the literature in multiple compound heterozygous individuals affected with Pendred Syndrome (e.g. GonzalezTrevino_2001) or with bilateral sensorineural hearing loss (e.g. Tang_2015, Cengiz_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28964290, 11375792, 25991456). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=3) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.

This is a predicted null variant in a splice site (PVS1). The GnomAD exomes allele frequency = 0.0000477 is less than 0.0001 threshold for the recessive gene, SLC26A4 (good GnomAD exomes coverage = 93.2), and the variant is not found in GnomAD genomes (PM2). Variant cited as pathogenic in PMIDs: 28964290 and 11748854. Predicted pathogenic in computational models (DANN, EIGEN, FATHMM-MKL and MutationTaster) with no benign predictions (PP3).

Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28964290, 25525159, 11375792, 21366435, 11748854)

This sequence change affects an acceptor splice site in intron 2 of the SLC26A4 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 SLC26A4 are known to be pathogenic (PMID: 16283880, 25394566, 26252218, 26445815). This variant is present in population databases (rs759792660, gnomAD 0.03%). Disruption of this splice site has been observed in individual(s) with Pendred syndrome (PMID: 11375792). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS2-1G>A. ClinVar contains an entry for this variant (Variation ID: 828068). 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.