ClinVar Miner

Submissions for variant NM_000153.4(GALC):c.884A>T (p.Asn295Ile)

dbSNP: rs746922378
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV000989251 SCV001139497 likely pathogenic Galactosylceramide beta-galactosidase deficiency 2019-05-28 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000989251 SCV002247060 pathogenic Galactosylceramide beta-galactosidase deficiency 2023-12-09 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 295 of the GALC protein (p.Asn295Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Krabbe disease (PMID: 30777126; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 803042). 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV000989251 SCV002512739 likely pathogenic Galactosylceramide beta-galactosidase deficiency 2021-03-16 criteria provided, single submitter clinical testing ACMG classification criteria: PS4 supporting, PM2 moderate, PP1, PP3 supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000989251 SCV002547866 likely pathogenic Galactosylceramide beta-galactosidase deficiency 2022-05-26 criteria provided, single submitter clinical testing Variant summary: GALC c.884A>T (p.Asn295Ile) 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 was absent in 248878 control chromosomes (gnomAD). The variant, c.884A>T, has been reported in the literature in at least one homozygous individuals affected with 'infantile' (or 'classic') Krabbe Disease (Beltran-Quintero_2019). These data indicate that the variant may be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated almost complete loss of activity for the variant protein (Saavedra-Matiz_2016). Three 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 (n=1) / likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000989251 SCV005635471 likely pathogenic Galactosylceramide beta-galactosidase deficiency 2024-04-10 criteria provided, single submitter clinical testing

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