Submissions for variant NM_000153.4(GALC):c.621G>A (p.Lys207=)

dbSNP: rs1428763453

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000664849	SCV000788868	uncertain significance	Galactosylceramide beta-galactosidase deficiency	2016-12-23	criteria provided, single submitter	clinical testing
Pathology and Clinical Laboratory Medicine, King Fahad Medical City	RCV000664849	SCV000996293	pathogenic	Galactosylceramide beta-galactosidase deficiency		criteria provided, single submitter	clinical testing	Enzyme deficiency
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193605	SCV001362550	uncertain significance	not specified	2019-03-07	criteria provided, single submitter	clinical testing	Variant summary: GALC c.621G>A (p.Lys207Lys) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: three predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 243894 control chromosomes (gnomAD). c.621G>A has been reported in the literature in a homozygous individual affected with Krabbe Disease (Wenger_2000), and in a newborn screening sample indicative of low GALC enzyme activity, where the a second mutation was not provided (Orsini_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Invitae	RCV000664849	SCV002135067	uncertain significance	Galactosylceramide beta-galactosidase deficiency	2023-06-29	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 550179). This variant has been observed in individual(s) with clinical features of Krabbe disease (PMID: 10833326, 26795590). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects codon 207 of the GALC mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GALC protein. This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon.
CeGaT Center for Human Genetics Tuebingen	RCV003886427	SCV004704449	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing	GALC: PM2, PP3, PP4
Natera, Inc.	RCV000664849	SCV002093649	uncertain significance	Galactosylceramide beta-galactosidase deficiency	2021-08-26	no assertion criteria provided	clinical testing