ClinVar Genomic variation as it relates to human health

Variant summary: The GALC c.136G>T (p.Asp46Tyr) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 9/149232 control chromosomes at a frequency of 0.0000603, which does not exceed the estimated maximal expected allele frequency of a pathogenic GALC variant (0.0022361). The variant was reported in several patients in compound heterozygosity with at least two likely pathogenic/pathogenic mutations and biochemical findings suggestive of Krabbe disease (Pchelina_2014; Zhao_2017). Per latest published reports, c.136G>T is associated with a mild clinical course of disease (Zhao_2017). Taken together, this variant is classified as Pathogenic.

The variant was co-segregated with Krabbe disease in multiple affected family members (PMID: 31185936, PP1_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.841, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000059, PM2_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000633229, PMID:24078576, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 25265039, 28598007, PM3_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 46 of the GALC protein (p.Asp46Tyr). This variant is present in population databases (rs751975987, gnomAD 0.06%). This missense change has been observed in individual(s) with Krabbe disease (PMID: 24078576, 28598007, 31185936; externalcommunication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 633229). 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%. For these reasons, this variant has been classified as Pathogenic.

Variant confirmed as disease-causing by referring clinical team

The GALC c.136G>T variant is predicted to result in the amino acid substitution p.Asp46Tyr. This variant has been reported in the compound heterozygous state in several individuals with Krabbe disease with the age of onset ranging from late-infantile to juvenile (Zhaung et al. 2019. PubMed ID: 31185936; Zhao et al. 2018. PubMed ID: 28598007; Pchelina et al. 2014. PubMed ID: 25265039). Individuals with this variant tend to have a milder clinical course of disease (Zhao et al. 2018. PubMed ID: 28598007; Zhaung et al. 2019. PubMed ID: 31185936). This variant has also been reported in the heterozygous state along with two benign polymorphisms in GALC in another individual with Krabbe disease (Da et al. 2013. PubMed ID: 24078576). This variant is reported in 0.061% of alleles in individuals of East Asian descent in gnomAD and interpreted as pathogenic in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/633229/). This variant is interpreted as pathogenic.