ClinVar Miner

Submissions for variant NM_000153.4(GALC):c.674C>A (p.Ala225Glu)

gnomAD frequency: 0.00002  dbSNP: rs373077659
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001237593 SCV001410359 pathogenic Galactosylceramide beta-galactosidase deficiency 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 225 of the GALC protein (p.Ala225Glu). This variant is present in population databases (rs373077659, gnomAD 0.002%). This missense change has been observed in individual(s) with Krabbe disease (PMID: 26795590, 30777126; Invitae). This variant is also known as c.626C>A p.Ala209Glu. ClinVar contains an entry for this variant (Variation ID: 963553). 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). This variant disrupts the p.Ala225 amino acid residue in GALC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26795590, 27638593, 30777126; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Natera, Inc. RCV001237593 SCV002093648 uncertain significance Galactosylceramide beta-galactosidase deficiency 2020-02-05 no assertion criteria provided clinical testing

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