Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000669147 | SCV000793864 | uncertain significance | Galactosylceramide beta-galactosidase deficiency | 2017-09-01 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000669147 | SCV003442795 | uncertain significance | Galactosylceramide beta-galactosidase deficiency | 2022-02-06 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 231 of the GALC protein (p.Glu231Lys). This variant is present in population databases (rs542231350, gnomAD 0.03%). This missense change has been observed in individual(s) with Krabbe disease (PMID: 8940268). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as E215K. ClinVar contains an entry for this variant (Variation ID: 553651). 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 not expected to disrupt GALC protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GALC function (PMID: 8940268, 27126738). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003226357 | SCV003922541 | uncertain significance | not specified | 2023-03-09 | criteria provided, single submitter | clinical testing | Variant summary: GALC c.691G>A (p.Glu231Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 249352 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GALC causing Krabbe Disease (4e-05 vs 0.0022), allowing no conclusion about variant significance. c.691G>A has been reported in the literature in individuals affected with late-onset globoid-cell leukodystrophy (GLD) (example: DeGasperi_1996). These report(s) do not provide unequivocal conclusions about association of the variant with Krabbe Disease. At least one publication reports experimental evidence evaluating an impact on protein function (examples: DeGasperi_1996, Spratley_2016). The most pronounced variant effect results in 70-85% of normal activity (DeGasperi_1996). Two ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. |