ClinVar Miner

Submissions for variant NM_000153.4(GALC):c.868C>T (p.Arg290Cys) (rs780750448)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota RCV000991305 SCV001142709 likely pathogenic Galactosylceramide beta-galactosidase deficiency 2019-07-03 criteria provided, single submitter clinical testing
Invitae RCV000991305 SCV001575452 likely pathogenic Galactosylceramide beta-galactosidase deficiency 2020-01-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 290 of the GALC protein (p.Arg290Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs780750448, ExAC 0.009%). This variant has been observed in individual(s) with Krabbe disease (PMID: 22115770). 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 c.820C>T (p.R274C) in the literature. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg290 amino acid residue in GALC. Other variant(s) that disrupt this residue have been observed in individuals with GALC-related conditions (PMID: 30777126), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence, RCV000991305 SCV001431227 likely pathogenic Galactosylceramide beta-galactosidase deficiency no assertion criteria provided clinical testing

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