14-87945631-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM5PP2PP3PP5_Very_Strong

The NM_000153.4(GALC):c.1592G>A(p.Arg531His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,610,354 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R531P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

GALC
NM_000153.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.70

Publications

10 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 14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000153.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-87945631-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 623356.

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, 0.816

PP5

Variant 14-87945631-C-T is Pathogenic according to our data. Variant chr14-87945631-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 167119.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.1592G>A	p.Arg531His	missense_variant	Exon 14 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.1592G>A	p.Arg531His	missense_variant	Exon 14 of 17	1	NM_000153.4	ENSP00000261304.2		P54803-1

Frequencies

GnomAD3 genomes

AF:

0.0000527

AC:

AN:

151924

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:

0.000972

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000522

AC:

AN:

248936

AF XY:

0.0000444

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000556

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000384

AC:

AN:

1458312

Hom.:

Cov.:

AF XY:

0.0000427

AC XY:

AN XY:

725744

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33354

American (AMR)

AF:

0.00

AC:

AN:

44610

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26068

East Asian (EAS)

AF:

0.000252

AC:

AN:

39676

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.0000334

AC:

AN:

1109012

Other (OTH)

AF:

0.0000996

AC:

AN:

60236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152042

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41510

American (AMR)

AF:

0.00

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000974

AC:

AN:

5134

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67954

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000920

Hom.:

Bravo

AF:

0.0000453

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000579

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency

Pathogenic:6

Feb 23, 2023

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Missense variant. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.61). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000167119). Different missense changes at the same codon (p.Arg531Cys, p.Arg531Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000188997, VCV001345348). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Aug 24, 2021

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GALC c.1592G>A (p.Arg531His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 248936 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GALC causing Krabbe Disease (5.2e-05 vs 0.0022), allowing no conclusion about variant significance. c.1592G>A has been reported in the literature in individuals affected with Krabbe Disease (Fu_1999, Xu_2006, Orsini_2016, Fu_2018). Functional studies show that the variant results in a galactocerebrosidase protein that gets trapped in the endoplasmic reticulum due to misfolding (Spratley_2016). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jul 20, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 531 of the GALC protein (p.Arg531His). This variant is present in population databases (rs200378205, gnomAD 0.05%). This missense change has been observed in individuals with Krabbe disease (PMID: 10234611, 16607461, 26795590, 28976722). This variant is also known as p.Arg515His. ClinVar contains an entry for this variant (Variation ID: 167119). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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). For these reasons, this variant has been classified as Pathogenic. -

Nov 01, 2021

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NM_000153.3(GALC):c.1592G>A(R531H) is a missense variant classified as likely pathogenic in the context of Krabbe disease. R531H has been observed in cases of with relevant disease (PMID: 10234611, 16607461, Zheng_2014_(no PMID; abstract)). Functional assessments of this variant are available in the literature (PMID: 10234611, 27126738). R531H has been observed in population frequency databases (gnomAD: EAS 0.04%). In summary, NM_000153.3(GALC):c.1592G>A(R531H) is a missense variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Apr 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:3

Jan 23, 2014

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 21, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Functional studies found this variant is associated with significantly reduced enzyme activity and impaired localization to the lysosome (PMID: 27126738, 10234611); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28552323, 24252386, 16607461, 10234611, 26795590, 28976722, 34426522, 35314707, 34531397, 27126738) -

Oct 07, 2020

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;.;.;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.82

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

M;.;.;.

PhyloP100

7.7

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-4.5

D;D;D;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.94

MVP

0.99

MPC

0.65

ClinPred

0.75

GERP RS

4.6

Varity_R

0.60

gMVP

0.88

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over