ClinVar Genomic variation as it relates to human health

Variant summary: ATP6V1B1 c.687+1G>T 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 5' canonical splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.2e-06 in 191488 control chromosomes. c.687+1G>T has been reported in the literature in multiple individuals affected with Renal Tubular Acidosis With Progressive Nerve Deafness, either at a homozygous state or at a compound heterozygous with second pathogenic variants (example, Karet_1999, Palazzo_2017, Ruf_2003). These data indicate that the variant is very 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: 9916796, 28233610, 12579397). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change affects a donor splice site in intron 7 of the ATP6V1B1 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 ATP6V1B1 are known to be pathogenic (PMID: 9916796, 18368028). 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 renal tubular acidosis with deafness (PMID: 9916796, 16433694, 22966473). It has also been observed to segregate with disease in related individuals. This variant is also known as intron 7: gt‚Üítt or IVS7+1G>T. ClinVar contains an entry for this variant (Variation ID: 2203081). 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.