NM_000153.4:c.205C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000153.4(GALC):c.205C>T(p.Arg69*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000192 in 1,611,090 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

GALC
NM_000153.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 5.10

Publications

2 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 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 14-87988514-G-A is Pathogenic according to our data. Variant chr14-87988514-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 195020.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.205C>T	p.Arg69*	stop_gained	Exon 2 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.205C>T	p.Arg69*	stop_gained	Exon 2 of 17	1	NM_000153.4	ENSP00000261304.2		P54803-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000804

AC:

AN:

248890

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000199

AC:

AN:

1459096

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726106

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33430

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39670

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86198

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000234

AC:

AN:

1109518

Other (OTH)

AF:

0.00

AC:

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.409

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:

0.0000132

AC:

AN:

151994

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74248

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41366

American (AMR)

AF:

0.00

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2094

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:

0.0000214

Hom.:

ExAC

AF:

0.00000828

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency

Pathogenic:5

Jul 15, 2015

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Oct 19, 2021

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 19, 2017

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.205C>T (p.Arg69X) variant results in a premature termination codon, predicted to cause a truncated or absent GALC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/119986 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic GALC variant (0.0022361). The variant was reported in multiple affected individuals in the literature, and was shown to result in <10% GALC activity in a functional study where the variant was expressed in COS1 cells (Saavedra-Matiz_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Aug 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg69*) in the GALC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GALC are known to be pathogenic (PMID: 7437911, 9272171, 16607461). This variant is present in population databases (rs771111145, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Krabbe disease (PMID: 20886637). ClinVar contains an entry for this variant (Variation ID: 195020). For these reasons, this variant has been classified as Pathogenic. -

Apr 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:4

Aug 16, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss-of-function is a known mechanism of disease, and published functional studies support a null allele (PMID: 27638593); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.157C>T, p.R53* due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 25525159, 27638593, 20886637) -

Aug 22, 2014

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 23, 2020

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GALC: PVS1, PM2, PM3:Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.97

PhyloP100

5.1

Vest4

0.98

GERP RS

5.7

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.010

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over