rs1555378534

Variant names:

• chr14-87939914-TA-T
• rs1555378534
• NM_000153.4:c.1901delT

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000153.4(GALC):​c.1901delT​(p.Leu634fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003844847: GALC activity measured in COS1 cells was reported as less than 10% of wild-type (Saavedra-Martiz_2016).". 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 criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.12
• Publications: 5 publications found

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]

GALC Gene-Disease associations (from GenCC):

• Krabbe disease

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ACMG classification

Our verdict: Pathogenic. The variant received 22 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 24 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV003844847: GALC activity measured in COS1 cells was reported as less than 10% of wild-type (Saavedra-Martiz_2016).
• 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 Pathogenic. ClinVar VariationId is 554777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000153.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	NM_000153.4	MANE Select	c.1901delT	p.Leu634fs	frameshift	Exon 16 of 17	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.1832delT	p.Leu611fs	frameshift	Exon 15 of 16	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.1823delT	p.Leu608fs	frameshift	Exon 16 of 17	NP_001188331.1	P54803-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	ENST00000261304.7	TSL:1 MANE Select	c.1901delT	p.Leu634fs	frameshift	Exon 16 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000921945.1		c.1862delT	p.Leu621fs	frameshift	Exon 15 of 16	ENSP00000592004.1
	GALC	ENST00000950382.1		c.1835delT	p.Leu612fs	frameshift	Exon 16 of 17	ENSP00000620441.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Galactosylceramide beta-galactosidase deficiency (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555378534; hg19: chr14-88406258;