ClinVar Genomic variation as it relates to human health

Variant summary: GALC c.908+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: Three predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 245538 control chromosomes. c.908+1G>A has been reported in the literature in individuals affected with Krabbe Disease (example, Puckett_2012, Duffner_2012, Africa_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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 although one submitter has classified the variant as likely pathogenic before 2014 using overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.

NM_000153.3(GALC):c.908+1G>A is a canonical splice variant classified as pathogenic in the context of Krabbe disease. c.908+1G>A has been observed in cases with relevant disease (PMID: 22115770, 22520351, 28547031). Functional assessments of this variant are not available in the literature. c.908+1G>A has been observed in population frequency databases (gnomAD: SAS 0.01%). In summary, NM_000153.3(GALC):c.908+1G>A is a canonical splice variant that has internal structural support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

A Heterozygous, Splice site donor variant c.908+1G>A in Exon 8 of the GALC gene. The observed variant has a minor allele frequency of 0.00002/% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/ Likely Pathogenic (Variation ID: 188815). The variant has been previously reported for Krabee disease by Puckett RL, et al., 2012.Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

This sequence change affects a donor splice site in intron 8 of the GALC 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 GALC are known to be pathogenic (PMID: 7437911, 9272171, 16607461). This variant is present in population databases (rs750524447, gnomAD 0.007%). Disruption of this splice site has been observed in individual(s) with Krabbe disease (PMID: 22115770, 22520351, 28547031). This variant is also known as c.860+1G>A. ClinVar contains an entry for this variant (Variation ID: 188815). 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.