ClinVar Genomic variation as it relates to human health

A variant that is likely pathogenic has been identified in the GALC gene. The Y490N variant has been reported previously in an individual with a clinical diagnosis of Krabbe disease who was compound heterozygous for Y490N and a second GALC variant; however, insufficient clinical information was provided to confirm diagnosis (Tappino et al., 2010). In vitro expression studies show that Y490N (referred to as Y474N due to alternative nomenclature) causes a reduction of GALC expression (Saavedra-Matiz et al., 2016). The Y490N variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y490N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GALC function (PMID: 27638593). 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. ClinVar contains an entry for this variant (Variation ID: 431995). This variant is also known as p.Tyr474Asn. This missense change has been observed in individual(s) with Krabbe disease (PMID: 20886637, 21824559). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 490 of the GALC protein (p.Tyr490Asn).

Variant summary: GALC c.1468T>A (p.Tyr490Asn) 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 was absent in 248974 control chromosomes. c.1468T>A has been reported in the literature in compound heterozygous individuals affected with adult-onset Krabbe Disease (e.g. Iacono_2022) or early infantile Krabbe Disease (e.g. Tappino_2010, Duffner_2011, Wright_2017, Beltran-Quintero_2019) with one report describing a patient asymptomatic apart from decreased GALC activity levels (e.g. Beltran-Quintero_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal GALC enzyme activity in vitro (e.g. Saavedra-Martiz_2016). The following publications have been ascertained in the context of this evaluation (PMID: 30777126, 21824559, 35013804, 27638593, 20886637, 28855403). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=1), likely pathogenic (n=1) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.