ClinVar Miner

Submissions for variant NM_000153.4(GALC):c.1541T>C (p.Phe514Ser)

gnomAD frequency: 0.00001  dbSNP: rs375867319
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000726405 SCV000344419 likely pathogenic not provided 2016-08-26 criteria provided, single submitter clinical testing
Invitae RCV000324608 SCV000627127 pathogenic Galactosylceramide beta-galactosidase deficiency 2023-11-14 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 514 of the GALC protein (p.Phe514Ser). This variant is present in population databases (rs375867319, gnomAD 0.003%). This missense change has been observed in individual(s) with Krabbe disease (PMID: 9338580; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Phe498Ser. ClinVar contains an entry for this variant (Variation ID: 289955). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GALC function (PMID: 27638593). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000726405 SCV001714487 likely pathogenic not provided 2019-06-09 criteria provided, single submitter clinical testing PM2, PM3, PP3, PP4, PP5
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000324608 SCV001821222 pathogenic Galactosylceramide beta-galactosidase deficiency 2021-08-12 criteria provided, single submitter clinical testing Variant summary: GALC c.1541T>C (p.Phe514Ser) 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 1.2e-05 in 248836 control chromosomes. c.1541T>C has been reported in the literature in individuals affected with Krabbe Disease along with a second pathogenic allele (Wegner_1997, Lissens_2007, Fiumara_2011, Puckett_2012). Transfection studies showed the variant to result in mock levels of enzyme activity (Saavedra-Martiz_2016). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity RCV000726405 SCV003832507 likely pathogenic not provided 2022-09-23 criteria provided, single submitter clinical testing
Natera, Inc. RCV000324608 SCV001454064 likely pathogenic Galactosylceramide beta-galactosidase deficiency 2020-09-16 no assertion criteria provided clinical testing

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