ClinVar Miner

Submissions for variant NM_000153.4(GALC):c.749T>C (p.Ile250Thr) (rs886039569)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000256130 SCV000322420 pathogenic not provided 2016-05-04 criteria provided, single submitter clinical testing The I250T pathogenic variant in the GALC gene has been reported previously, using alternate nomenclature (I234T), in the homozygous and compound heterozygous states in multiple individuals with Krabbe disease (De Gasperi et al., 1996; Dimitriou et al., 2015; Gucev et al., 2015). Dimitriou et al. (2015) reported I250T as the most common pathogenic variant found in a study of Greek individuals with Krabbe disease. The I250T variant was not observed in approximately 6100 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 I250T 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. Expression studies in COS-1 cells and in the human CNS-derived cell line, H4, show nearly complete loss of normal galactocerebrosidase activity (De Gasperi et al., 1996; Lee et al., 2010). Therefore,we interpret I250T as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000984177 SCV001251627 pathogenic Galactosylceramide beta-galactosidase deficiency 2020-02-13 criteria provided, single submitter clinical testing The GALC c.749T>C (p.Ile250Thr) variant is a missense variant that has been recognized as a common variant in individuals with Krabbe disease who are of Greek ancestry. Across a selection of the available literature, this variant, which was previously referred to as p.Ile234Thr, has been reported in a homozygous state in at least four unrelated individuals and in a compound heterozygous state in two individuals (De Gasperi et al. 1996; Dimitriou et al. 2016). The variant also segregated with the disease in one additional affected individual. Age of onset was in the neonatal period or first few years of life. Functional studies in COS cells and in the human CNS-derived cell line H4 demonstrated negligible residual enzyme activity compared to WT as well as disrupted precursor processing (De Gasperi et al. 1996; Lee et al. 2010). Based on the collective evidence, the p.Ile250Thr variant is classified as pathogenic for Krabbe disease.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000984177 SCV001370000 likely pathogenic Galactosylceramide beta-galactosidase deficiency 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP2,PP3.
Counsyl RCV000984177 SCV001132201 pathogenic Galactosylceramide beta-galactosidase deficiency 2016-11-16 no assertion criteria provided clinical testing
Natera, Inc. RCV000984177 SCV001454070 pathogenic Galactosylceramide beta-galactosidase deficiency 2020-09-16 no assertion criteria provided clinical testing

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