rs145580093

Positions:

• chr14-87986582-T-A
• chr14-87986582-T-C
• chr14-87986582-T-G

Variant summary

Our verdict is Pathogenic. Variant got 24 ACMG points: 24P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The ENST00000261304.7(GALC):​c.349A>T​(p.Met117Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M117V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GALC ENST00000261304.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.99

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 24 ACMG points.

• PS1: Transcript ENST00000261304.7 (GALC) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 1066196
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000261304.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-87986582-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 92504.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=3, Uncertain_significance=2}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856
• PP5: Variant 14-87986582-T-A is Pathogenic according to our data. Variant chr14-87986582-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1458657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALC	NM_000153.4	c.349A>T	p.Met117Leu	missense_variant	4/17	ENST00000261304.7	NP_000144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7	c.349A>T	p.Met117Leu	missense_variant	4/17	1	NM_000153.4	ENSP00000261304	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 10, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met117 amino acid residue in GALC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23430802, 27638593, 30089515). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Studies have shown that this missense change alters GALC gene expression (PMID: 8940268). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GALC protein function. This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 117 of the GALC protein (p.Met117Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Krabbe disease (PMID: 8940268). This variant is also known as M101L. ClinVar contains an entry for this variant (Variation ID: 1458657). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 15, 2023	Variant summary: GALC c.349A>T (p.Met117Leu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249238 control chromosomes. c.349A>T has been reported in the literature as a compound heterozygous genotype with a null allele variant in at-least one individual affected with a late-onset form of Krabbe Disease (example, De Gaspieri_1996 cited in Iacono_2022). At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 20% of normal galactocerebrosidase activity in-vitro (De Gaspieri_1996) and a 94% reduction in GALC activity in the brain homogenate of the individual reported above (Iacono_2022 citing De Gaspieri_1996). The following publications have been ascertained in the context of this evaluation (PMID: 8940268, 21876145, 36113749). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.88	D;.;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.1	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.5	D;D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.018	D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.81
MutPred		0.76		Gain of catalytic residue at E113 (P = 0.002);.;.;.;
MVP		0.88
MPC		0.57
ClinPred		0.98	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-88452926;