ClinVar Miner

Submissions for variant NM_000153.4(GALC):c.857G>A (p.Gly286Asp) (rs199847983)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000023593 SCV000220193 likely pathogenic Galactosylceramide beta-galactosidase deficiency 2014-03-31 criteria provided, single submitter literature only
GeneDx RCV000363446 SCV000329642 pathogenic not provided 2018-10-19 criteria provided, single submitter clinical testing The G286D pathogenic variant in the GALC gene has been reported previously (as G270D due to alternative nomenclature) in association with late-onset Krabbe disease when present in the homozygous state or when in trans with another pathogenic variant (Xu et al., 2006; Tappino et al., 2010; Hossain et al., 2014) and has been demonstrated to result in decreased activity of the GALC enzyme (De Gasperi et al., 1999; Hossain et al., 2014). The G286D variant was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G286D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. We interpret G286D as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000023593 SCV000695679 pathogenic Galactosylceramide beta-galactosidase deficiency 2016-05-13 criteria provided, single submitter clinical testing Variant summary: The GALC c.857G>A (p.Gly286Asp) variant causes a missense change involving a conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a "damaging" outcome. This variant was found in the large, broad control population, ExAC, with an allele frequency of 4/120630 (1/30120, frequency: 0.0000332), which does not exceed the estimated maximal expected allele frequency for a pathogenic GALC variant of 1/447 (0.0022361). The variant of interest has been reported in multiple affected individuals via publications that also show a significant decrease in GALC activity. Authors do suggest the variant of interest to be associated with a juvenile/mild form of Krabbe disease due to multiple individuals being diagnosed at a later stage in life (~60 years old) (Furuya_1997 and Tappino_2010). Multiple databases/clinical laboratories cite the variant as "likely pathogenic/pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.
Invitae RCV000023593 SCV000937025 pathogenic Galactosylceramide beta-galactosidase deficiency 2018-10-03 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 286 of the GALC protein (p.Gly286Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs199847983, ExAC 0.006%). This variant has been observed in several individuals affected with GALC-related condition (PMID: 9272171, 27780934, 28547031, 28600779, 10477434, 23430802, 20886637). This variant is also known as G270D in the literature. ClinVar contains an entry for this variant (Variation ID: 30619). Experimental studies have shown that this missense change has a deleterious effect on protein function (PMID: 9272171, 25956830, 26865610, 27126738, 27638593). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000023593 SCV000044884 pathogenic Galactosylceramide beta-galactosidase deficiency 2010-12-01 no assertion criteria provided literature only

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