ClinVar Genomic variation as it relates to human health

NM_000153.3(GALC):c.1592G>A(R531H) is a missense variant classified as likely pathogenic in the context of Krabbe disease. R531H has been observed in cases of with relevant disease (PMID: 10234611, 16607461, Zheng_2014_(no PMID; abstract)). Functional assessments of this variant are available in the literature (PMID: 10234611, 27126738). R531H has been observed in population frequency databases (gnomAD: EAS 0.04%). In summary, NM_000153.3(GALC):c.1592G>A(R531H) is a missense variant that has functional 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.

Functional studies found this variant is associated with significantly reduced enzyme activity and impaired localization to the lysosome (Fu et al., 1999; Spratley et al. 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28552323, 24252386, 16607461, 10234611, 26795590, 28976722, 34426522, 35314707, 34531397, 27126738)

Variant summary: GALC c.1592G>A (p.Arg531His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 248936 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GALC causing Krabbe Disease (5.2e-05 vs 0.0022), allowing no conclusion about variant significance. c.1592G>A has been reported in the literature in individuals affected with Krabbe Disease (Fu_1999, Xu_2006, Orsini_2016, Fu_2018). Functional studies show that the variant results in a galactocerebrosidase protein that gets trapped in the endoplasmic reticulum due to misfolding (Spratley_2016). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Missense variant. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.61). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000167119). Different missense changes at the same codon (p.Arg531Cys, p.Arg531Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000188997, VCV001345348). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 531 of the GALC protein (p.Arg531His). This variant is present in population databases (rs200378205, gnomAD 0.05%). This missense change has been observed in individuals with Krabbe disease (PMID: 10234611, 16607461, 26795590, 28976722). This variant is also known as p.Arg515His. ClinVar contains an entry for this variant (Variation ID: 167119). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GALC protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GALC function (PMID: 27126738). For these reasons, this variant has been classified as Pathogenic.