rs138577661

chr14-87939915-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 13P and 1B. PM1 PM2 PP3 PP5_Very_Strong BP4

The NM_000153.4(GALC):c.1901T>C(p.Leu634Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000246 in 1,607,104 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L634L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: GALC NM_000153.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 B:1 O:1
• Conservation: PhyloP100: 7.12

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 12 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, 5 uncertain in NM_000153.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, M_CAP, MutationAssessor, PROVEAN, REVEL [when FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 14-87939915-A-G is Pathogenic according to our data. Variant chr14-87939915-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.113942355).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALC	NM_000153.4	c.1901T>C	p.Leu634Ser	missense_variant	16/17	ENST00000261304.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALC	ENST00000261304.7	c.1901T>C	p.Leu634Ser	missense_variant	16/17	1	NM_000153.4	P1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 151950 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00870

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

GnomAD3 exomes AF: 0.000651 AC: 162 AN: 248814 Hom.: 0 AF XY: 0.000615 AC XY: 83 AN XY: 135016

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00851

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000241 AC: 351 AN: 1455036 Hom.: 1 Cov.: 29 AF XY: 0.000250 AC XY: 181 AN XY: 724352

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00790

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.000283

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152068 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74336

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00872

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000444 Hom.: 1

Bravo AF: 0.000495

ExAC AF: 0.000687 AC: 83

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Benign:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Pathogenic:9 Benign:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jan 11, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 05, 2019	Across a selection of the available literature, the GALC c.1901T>C (p.Leu634Ser) missense variant, also referred to as p.Leu618Ser, has been identified in 12 individuals affected with Krabbe disease, including in a homozygous state in one individual, in a compound heterozygous state in eight individuals, and in a heterozygous state in three individuals. All affected individuals were of Asian descent and have a variable age of onset of Krabbe disease ranging from late-infantile to adult (Furuya et al. 1997; Satoh et al. 1997; Xu et al. 2006; Hossain et al. 2014; Lim et al. 2016; Yoshimura et al. 2016). The p.Leu634Ser variant was also reported in seven asymptomatic newborns including in five in a homozygous state and in two in a compound heterozygous state (Orsini et al. 2016). In the five asymptomatic homozygous newborns, additional GALC variants were detected in cis with the p.Leu634Ser variant. GALC activity was used to assess risk of developing Krabbe disease, with one infant classified as high-risk, one as low-risk, and three as moderate-risk (Orsini et al. 2016). The p.Leu634Ser variant was absent from 65 controls (Furuya et al. 1997), but is reported at a frequency of 0.01923 in the Japanese population of the 1000 Genomes Project. Expression of the p.Leu634Ser variant in COS-1 cells resulted in an approximately 90% reduction in enzyme activity when compared to wild-type (Furuya et al. 1997; Satoh et al. 1997; Shin et al. 2016). Another study demonstrated lack of secretion of the p.Leu634Ser variant protein in transfected HEK293T cells, and also suggested that presence of the variant reduced trafficking of the GALC protein to lysosomes, although a second study showed localization in lysosomes (Spratley et al. 2016; Shin et al. 2016). Despite the high allele frequency, based on the collective clinical evidence, the p.Leu634Ser variant is classified as likely pathogenic for Krabbe disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 634 of the GALC protein (p.Leu634Ser). This variant is present in population databases (rs138577661, gnomAD 0.9%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Krabbe disease (PMID: 9272171, 16607461, 24252386, 26865610, 27679535, 27780934). This variant is also known as Leu618Ser. ClinVar contains an entry for this variant (Variation ID: 225368). 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: 9272171, 24252386, 27126738, 27638593, 27780934). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 12, 2016	Variant summary: The GALC c.1901T>C (p.Leu634Ser) variant, alternatively also known was L618S, involves the alteration of a highly conserved nucleotide and is located in Glyco_hydro_59 domain of the protein. 4/4 in silico tools predict a damaging outcome for this variant. This variant was found in 83/120532 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0090487 (78/8620). No homozygotes have been reported in general population. In literature, this variant is widely reported as a mild pathogenic variant that causes later-onset Krabbe disease (KD) and is found in several KD patients in homozygous, compound heterozygous and heterozygous states. The variants frequency is high in Japanese patients; a study has reported its allele frequency at 10.7% (11/102 alleles) in a Japanese patient cohort (Hossain_2013). Available functional assays (enzymatic as well as processing assay) further support the variant as a pathogenic variant with ~10% GALC activity in transfected cells. There is some conflicting functional data on the proper localization of the mutant with Shin_2016 and Lim_2016 reporting proper localization while Spratley_2016 reports improper localization. Taken together, this variant is classified as Pathogenic. -
Benign, flagged submission	clinical testing	Center for Molecular Medicine, Children’s Hospital of Fudan University	May 10, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 31, 2019	NM_000153.3(GALC):c.1901T>C(L634S) is classified as pathogenic in the context of Krabbe disease and may be associated with a late-onset form of disease. Sources cited for classification include the following: PMID 29951496, 29966168, 30089515, 27638604, 26865610, 27126738, 24252386, 9272171, 26795590, 27780934 and 27679535. Classification of NM_000153.3(GALC):c.1901T>C(L634S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
not provided, no classification provided	literature only	GeneReviews	-	One copy of this allele together with another severe allele in the homozygous state is associated with late-onset disease. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 12, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 28, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;T;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.1	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.5	D;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.99
MVP		0.98
MPC		0.69
ClinPred		0.19	T
GERP RS		5.8
Varity_R		0.76
gMVP		0.99

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

Other links and lift over

dbSNP: rs138577661; hg19: chr14-88406259;