ClinVar Miner

Submissions for variant NM_000153.4(GALC):c.1657G>A (p.Gly553Arg) (rs748573754)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169525 SCV000221002 likely pathogenic Galactosylceramide beta-galactosidase deficiency 2014-12-31 criteria provided, single submitter literature only
Invitae RCV000169525 SCV001203582 pathogenic Galactosylceramide beta-galactosidase deficiency 2019-03-03 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 553 of the GALC protein (p.Gly553Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs748573754, ExAC 0.002%). This variant has been observed in several individuals affected with Krabbe disease (PMID: 10477434, 20886637). This variant is also known as c.1609G>A (p.Gly537Arg) in the literature. ClinVar contains an entry for this variant (Variation ID: 189113). This variant has been reported to affect GALC protein function (PMID: 10477434, 27638593). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169525 SCV001442678 pathogenic Galactosylceramide beta-galactosidase deficiency 2020-10-02 criteria provided, single submitter clinical testing Variant summary: GALC c.1657G>A (p.Gly553Arg) 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 allele was found at a frequency of 8e-06 in 248898 control chromosomes. c.1657G>A has been reported in the literature in multiple individuals affected with Krabbe Disease (example, DeGasperi_1999, Tappino_2010). These data indicate that the variant is very 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% of normal GALC activity in an in-vitro assay (De Gasperi_1999). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc. RCV000169525 SCV001454062 pathogenic Galactosylceramide beta-galactosidase deficiency 2020-09-16 no assertion criteria provided clinical testing

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