rs1555378534

Positions:

• chr14-87939914-TA-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000153.4(GALC):​c.1901del​(p.Leu634Ter) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L634L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GALC NM_000153.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.12

Genes affected

GALC (HGNC:4115): (galactosylceramidase) This gene encodes a lysosomal protein which hydrolyzes the galactose ester bonds of galactosylceramide, galactosylsphingosine, lactosylceramide, and monogalactosyldiglyceride. Mutations in this gene have been associated with Krabbe disease, also known as globoid cell leukodystrophy. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 20 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-87939914-TA-T is Pathogenic according to our data. Variant chr14-87939914-TA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 554777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALC	NM_000153.4	c.1901del	p.Leu634Ter	frameshift_variant	16/17	ENST00000261304.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALC	ENST00000261304.7	c.1901del	p.Leu634Ter	frameshift_variant	16/17	1	NM_000153.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 22, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the GALC protein in which other variant(s) (p.Val681Met) have been determined to be pathogenic (PMID: 23462331, 31885218). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 554777). This variant is also known as 1852delT (Leu618X). This premature translational stop signal has been observed in individual(s) with GALC-related conditions (PMID: 9338580, 29951496). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu634*) in the GALC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 52 amino acid(s) of the GALC protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 03, 2023	Variant summary: GALC c.1901delT (p.Leu634X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory and reported in HGMD in association with Krabbe disease. The variant was absent in 248794 control chromosomes. c.1901delT has been reported in the literature in individuals affected with Krabbe Disease (eg. Wegner_1997, Tappino_2010, Zhang_2021, Guenzel_2020, etc). These data indicate that the variant is likely to be associated with disease. GALC activity measured in COS1 cells was reported as less than 10% of wild-type (Saavedra-Martiz_2016). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 03, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2010	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555378534; hg19: chr14-88406258;