ClinVar Miner

Submissions for variant NM_000153.4(GALC):c.582+1G>A

gnomAD frequency: 0.00001  dbSNP: rs750881596
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001378267 SCV001575803 likely pathogenic Galactosylceramide beta-galactosidase deficiency 2024-01-04 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 of the GALC gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GALC are known to be pathogenic (PMID: 7437911, 9272171, 16607461). This variant is present in population databases (rs750881596, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with Krabbe disease (PMID: 31395954). ClinVar contains an entry for this variant (Variation ID: 1067095). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001378267 SCV003800661 likely pathogenic Galactosylceramide beta-galactosidase deficiency 2023-01-12 criteria provided, single submitter clinical testing Variant summary: GALC c.582+1G>A is located in a canonical splice-site and may affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. 4/4 computational tools via alamut predict no impact on splicing at the canonical wild type and the mutant location. This precludes an exact estimation of the computational splicing impact. The variant allele was found at a frequency of 4e-06 in 248874 control chromosomes. c.582+1G>A has been reported in the literature in at least one individual in an infant death cohort, however without strong evidence for causalilty (lack of co-segregation, co-occurrence, and phenotypic data) (e.g., Wojcik_2020). This report therefore does not provide unequivocal conclusions about association of the variant with Krabbe Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Revvity Omics, Revvity RCV003490236 SCV004238206 likely pathogenic not provided 2023-07-19 criteria provided, single submitter clinical testing

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