14-87992996-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000153.4(GALC):c.169G>A(p.Gly57Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000013 in 1,534,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G57R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

GALC
NM_000153.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 6.91

Publications

9 publications found

Variant links:

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: G2P, Myriad Women’s Health, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Genomics England PanelApp

GALC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000153.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-87992996-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1324445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 94 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 0.18582 (below the threshold of 3.09). Trascript score misZ: -0.28853 (below the threshold of 3.09). GenCC associations: The gene is linked to Krabbe disease.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.955

PP5

Variant 14-87992996-C-T is Pathogenic according to our data. Variant chr14-87992996-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 193054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALC	NM_000153.4 link	c.169G>A	p.Gly57Ser	missense_variant	Exon 1 of 17	ENST00000261304.7	NP_000144.2	P54803-1A0A0A0MQV0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7 link	c.169G>A	p.Gly57Ser	missense_variant	Exon 1 of 17	1	NM_000153.4	ENSP00000261304.2		P54803-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.23e-7

AC:

AN:

1382938

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

684314

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28544

American (AMR)

AF:

0.00

AC:

AN:

37248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24340

East Asian (EAS)

AF:

0.00

AC:

AN:

33536

South Asian (SAS)

AF:

0.00

AC:

AN:

78516

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37834

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4108

European-Non Finnish (NFE)

AF:

9.25e-7

AC:

AN:

1081556

Other (OTH)

AF:

0.00

AC:

AN:

57256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152052

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41408

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67984

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Oct 16, 2014

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 29, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect: cells expressing the G57S variant have undetectable GALC activity in comparison to wild type (Lissens et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Also known as Gly41Ser (G41S); This variant is associated with the following publications: (PMID: 27638593, 27126738, 17579360, 21070211) -

Mar 31, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Galactosylceramide beta-galactosidase deficiency

Pathogenic:2Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Mar 10, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The GALC c.169G>A variant affects a conserved nucleotide, resulting in amino acid change from Gly to Ser. 5/5 in-silico tools predict damaging outcome for this variant. This variant has been reported in at least 5 patients with late onset Krabbe disease in both homozygous and compound heterozygous state. This variant was not found in 16310 control chromosomes. In addition, one clinical laboratory classified this variant as pathogenic. Taken together, this variant was classified as pathogenic. -

Dec 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 57 of the GALC protein (p.Gly57Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Krabbe disease (PMID: 17579360, 21070211). This variant is also known as c.121G>A; p.Gly41Ser. ClinVar contains an entry for this variant (Variation ID: 193054). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GALC function (PMID: 27126738). This variant disrupts the p.Gly57 amino acid residue in GALC. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;.

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Uncertain

2.3

M;M

PhyloP100

6.9

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-4.8

D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.010

D;D

Polyphen

1.0

D;.

Vest4

0.97

MutPred

0.79

Gain of catalytic residue at S62 (P = 2e-04);Gain of catalytic residue at S62 (P = 2e-04);

MVP

1.0

MPC

0.53

ClinPred

1.0

GERP RS

3.2

PromoterAI

-0.031

Neutral

(source)

Varity_R

0.73

gMVP

0.96

Mutation Taster

=14/86

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over