ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 372 of the GALC protein (p.Ala372Ser). This variant is present in population databases (rs759286485, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with GALC-related conditions. ClinVar contains an entry for this variant (Variation ID: 885479). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Variant summary: GALC c.1114G>T (p.Ala372Ser) results in a conservative amino acid change located in the Glycosyl hydrolase family 59, central domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 249116 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1114G>T has been reported in the literature in individuals affected with Krabbe Disease. These report(s) do not provide unequivocal conclusions about association of the variant with low GALC activity (Orsini_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26795590). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Krabbe disease (MIM#245200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 8 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3: 10 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Glyco_hydro_59M (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. A change to threonine has been reported in ClinVar as VUS by diagnostic laboratories. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been detected in a newborn screening cohort in a baby with low GALC activity, however it is unclear whether a second hit was identified (PMID: 26795590). In addition, it has been regarded as a VUS in ClinVar by multiple diagnostic laboratories. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign