ClinVar Miner

Submissions for variant NM_000153.4(GALC):c.1468T>A (p.Tyr490Asn) (rs202135871)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498864 SCV000589634 likely pathogenic not provided 2017-06-21 criteria provided, single submitter clinical testing 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.
Counsyl RCV000668258 SCV000792831 uncertain significance Galactosylceramide beta-galactosidase deficiency 2017-07-17 criteria provided, single submitter clinical testing
Invitae RCV000668258 SCV001419281 pathogenic Galactosylceramide beta-galactosidase deficiency 2020-08-10 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with asparagine at codon 490 of the GALC protein (p.Tyr490Asn). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Krabbe disease (PMID: 20886637, 21824559). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Tyr474Asn in the literature. ClinVar contains an entry for this variant (Variation ID: 431995). This variant has been reported to affect GALC protein function (PMID: 27638593). For these reasons, this variant has been classified as Pathogenic.

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