ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs886039569
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000256130 SCV000322420 pathogenic not provided 2019-12-11 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 8940268, 30209698, 20410102, 25525159, 20886637, no PMID, 27442402, 27638593, 27785412, 26108647, 33190188)
Illumina Laboratory Services, 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.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV000984177 SCV001976851 pathogenic Galactosylceramide beta-galactosidase deficiency 2021-10-05 criteria provided, single submitter clinical testing PM2, PP2, PP3, PM3, PP5
Invitae RCV000984177 SCV002246695 pathogenic Galactosylceramide beta-galactosidase deficiency 2024-01-08 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 250 of the GALC protein (p.Ile250Thr). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with Krabbe disease (PMID: 8940268, 27442402). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.701T>C (p.I234T). ClinVar contains an entry for this variant (Variation ID: 265479). 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: 8940268). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000256130 SCV003825716 pathogenic not provided 2022-12-08 criteria provided, single submitter clinical testing
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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.