rs1249991480

Positions:

chr14-87934841-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_000153.4(GALC):c.1949T>C(p.Leu650Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,756 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 Conflicting classifications of pathogenicity (no stars).

Frequency

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

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GALC
NM_000153.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:7

Conservation

PhyloP100: 8.10

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

PP5

Variant 14-87934841-A-G is Pathogenic according to our data. Variant chr14-87934841-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 555965.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALC	NM_000153.4 linkuse as main transcript	c.1949T>C	p.Leu650Pro	missense_variant	17/17	ENST00000261304.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALC	ENST00000261304.7 linkuse as main transcript	c.1949T>C	p.Leu650Pro	missense_variant	17/17	1	NM_000153.4	P1	P54803-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152096

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

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

247910

Hom.:

AF XY:

0.00000743

AC XY:

AN XY:

134574

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000894

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460660

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726674

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency

Pathogenic:1Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 29, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 24, 2023	ClinVar contains an entry for this variant (Variation ID: 555965). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects GALC function (PMID: 27638593). 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 variant is also known as p.L634P. This missense change has been observed in individual(s) with Krabbe disease (PMID: 30089515). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 650 of the GALC protein (p.Leu650Pro). -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 08, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 06, 2023	Criteria applied: PS3_MOD,PM3,PM2_SUP,PP3 -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 02, 2022	PP3, PM2_SUP -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 10, 2023	- -

See cases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

May 24, 2023

ACMG categories: PM2,PM3,PP3,PP4 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 15, 2021

Variant summary: GALC c.1949T>C (p.Leu650Pro) (legacy name p.Leu634Pro) 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 4e-06 in 247910 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1949T>C has always been reported in the literature as a complex allele in combination with another variant, p.Ile562Thr (legacy name p.Ile546Thr) in settings of newborn screening for Krabbe's disease and in compound heterozygosity with another complex allele combination in at-least one individual affected with Krabbe Disease (example, Saavendra-Matiz_2016, Bascou_2018). These report(s) do not provide unequivocal conclusions about association of the variant in isolation with Krabbe Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

D;.;.

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.68

T;T;T

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

2.9

M;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.48

PROVEAN

Uncertain

-4.2

D;D;D

REVEL

Pathogenic

0.93

Sift

Uncertain

0.010

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

0.99

D;D;.

Vest4

0.95

MutPred

0.76

Gain of catalytic residue at W651 (P = 0.0017);.;.;

MVP

1.0

MPC

0.70

ClinPred

0.99

GERP RS

5.6

Varity_R

0.85

gMVP

0.98

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over