ClinVar Genomic variation as it relates to human health

This sequence change affects a donor splice site in intron 4 of the GOSR2 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 GOSR2 are known to be pathogenic (PMID: 21549339). This variant is present in population databases (rs141554661, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with a diagnosis of, or clinical features of, muscular dystrophy (PMID: 25326637; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 211092). 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 c.336+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 4 of the GOSR2 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.

Reported in an individual with congenital muscular dystrophy and myoclonic epilepsy who was heterozygous for c.336+1 G>A and another GOSR2 pathogenic variant (Tsai et al, 2013); 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: 32105965, 25326637, 34426522, 31980526, 31345219, 31440721)

Variant summary: GOSR2 c.336+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 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0001 in 250474 control chromosomes. c.336+1G>A has been reported in the literature in compound heterozygous individuals affected with progressive myoclonus epilepsy with neurodegeneration or congenital muscular dystrophy, or in a heterozygous individual affected with epilepsy without evidence of causality (e.g. Truty_2019, Stemmerik_2021, Hentrich_2023). 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: 37895210, 34167170, 31440721). ClinVar contains an entry for this variant (Variation ID: 211092). Based on the evidence outlined above, the variant was classified as likely pathogenic.

PM2, PM3, PVS1_strong