ClinVar Miner

Submissions for variant NM_000153.4(GALC):c.1158_1161+6del (rs759068540)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000513102 SCV000608710 uncertain significance not provided 2017-02-01 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000513102 SCV000701445 pathogenic not provided 2016-08-17 criteria provided, single submitter clinical testing
Invitae RCV001044546 SCV001208350 pathogenic Galactosylceramide beta-galactosidase deficiency 2019-12-13 criteria provided, single submitter clinical testing This variant results in the deletion of part of exon 10 (c.1158_1161+6del) of the GALC gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individual(s) with Krabbe disease (PMID: 21824559). This variant is also known as c.1110_1113+6del in the literature. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in GALC are known to be pathogenic (PMID: 7437911, 9272171, 16607461). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001044546 SCV001339011 pathogenic Galactosylceramide beta-galactosidase deficiency 2020-03-02 criteria provided, single submitter clinical testing Variant summary: GALC c.1158_1161+6del10 is located in the end of exon 10 including a canonical splice-site at intron 10 and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. 4/4 computational tools predict a significant impact on normal splicing and predict the variant abolishes a canonical 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 248926 control chromosomes (gnomAD). c.1158_1161+6del10 has been reported in the literature in individuals affected with Krabbe Disease (Duffner_2011, Beltran-Quintero_2019). These data indicate that the variant may be associated with disease. At least one in vitro study reports this variant effect results in decreasing normal GALC activity. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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