ClinVar Miner

Submissions for variant NM_000153.4(GALC):c.2041G>A (p.Val681Met)

gnomAD frequency: 0.00004  dbSNP: rs200607029
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center RCV000206966 SCV000267330 likely pathogenic Galactosylceramide beta-galactosidase deficiency 2016-03-18 criteria provided, single submitter reference population
Baylor Genetics RCV000206966 SCV001163744 likely pathogenic Galactosylceramide beta-galactosidase deficiency criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001093132 SCV001249964 likely pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001824669 SCV002074500 uncertain significance not specified 2023-05-10 criteria provided, single submitter clinical testing Variant summary: GALC c.2041G>A (p.Val681Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 248920 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GALC causing Krabbe Disease (0.00019 vs 0.0022), allowing no conclusion about variant significance. c.2041G>A has been reported in the literature as a compound heterozygous genotype in two individuals affected with adult onset presentations of Krabbe Disease (example, Yang_2013, Xie_2020) and one case of Krabbe Diasese diagnosed at newborn screening (Li_2022). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Saavendra-Matiz_2016). These results showed no damaging effect of this variant in isolation but when associated in cis with a different variant, namely p.I546T, a "haplotype effect" was observed such that the construct bearing p.V665M+p.I546T in cis demonstrated GALC enzyme activity of approximately 30% of normal WT levels. This variant is characterized as a mild allele when in cis with p.I546T. Lastly, the presence of this co-occurring allele in the three ascertained cases mentioned above cannot be unequivocally ruled out. The following publications have been ascertained in the context of this evaluation (PMID: 35419325, 27638593, 31885218, 23462331). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=4) and VUS (n=1). Based on the evidence outlined above, the variant in isolation was classified as VUS-possibly pathogenic.
Invitae RCV000206966 SCV002240802 pathogenic Galactosylceramide beta-galactosidase deficiency 2024-01-17 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 681 of the GALC protein (p.Val681Met). This variant is present in population databases (rs200607029, gnomAD 0.1%). This missense change has been observed in individual(s) with Krabbe disease (PMID: 23462331, 31885218). 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: 208291). 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 80%. For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center RCV000206966 SCV002579765 pathogenic Galactosylceramide beta-galactosidase deficiency 2022-02-24 criteria provided, single submitter clinical testing
Revvity Omics, Revvity Omics RCV001093132 SCV003808553 uncertain significance not provided 2022-11-16 criteria provided, single submitter clinical testing
GeneDx RCV001093132 SCV004168111 uncertain significance not provided 2023-05-11 criteria provided, single submitter clinical testing The significance of this variant, alone or in cis with another variant is not clear at present (PMID: 27638593); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as p.(V665M); This variant is associated with the following publications: (PMID: 34426522, 31589614, 36161165, 36341094, 23462331, 31885218, 35419325, 27638593)
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000206966 SCV000244018 uncertain significance Galactosylceramide beta-galactosidase deficiency 2013-06-27 no assertion criteria provided literature only

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.