Submissions for variant NM_000153.4(GALC):c.1671-1G>A

gnomAD frequency: 0.00002  dbSNP: rs1182103005

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779148	SCV000915658	uncertain significance	Galactosylceramide beta-galactosidase deficiency	2017-04-28	criteria provided, single submitter	clinical testing	This variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change. No publications were found based on this search. Due to the potential impact of splice acceptor variants and the lack of clarifying evidence, this variant is classified as a variant of uncertain significance but suspicious for pathogenicity for this disease.
Myriad Genetics, Inc.	RCV000779148	SCV002060034	pathogenic	Galactosylceramide beta-galactosidase deficiency	2021-11-17	criteria provided, single submitter	clinical testing	NM_000153.3(GALC):c.1671-1G>A is a canonical splice variant classified as pathogenic in the context of Krabbe disease. c.1671-1G>A has been observed in cases with relevant disease (PMID: 32089546). Functional assessments of this variant are not available in the literature. c.1671-1G>A has been observed in population frequency databases (gnomAD: ASJ 0.01%). In summary, NM_000153.3(GALC):c.1671-1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Invitae	RCV000779148	SCV002204871	pathogenic	Galactosylceramide beta-galactosidase deficiency	2023-09-12	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 14 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 (no rsID available, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with Krabbe disease (PMID: 32089546). ClinVar contains an entry for this variant (Variation ID: 632221). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.