rs770485731

chr14-87950724-G-Achr14-87950724-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000153.4(GALC):c.1186C>T(p.Arg396Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,599,058 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. R396Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: GALC NM_000153.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 1.58

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 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr14-87950723-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 556049.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 14-87950724-G-A is Pathogenic according to our data. Variant chr14-87950724-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 456712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALC	NM_000153.4	c.1186C>T	p.Arg396Trp	missense_variant	11/17	ENST00000261304.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALC	ENST00000261304.7	c.1186C>T	p.Arg396Trp	missense_variant	11/17	1	NM_000153.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000276 AC: 4 AN: 145134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000144

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: 0.0000301

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000161 AC: 4 AN: 248096 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134674

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000131 AC: 19 AN: 1453924 Hom.: 0 Cov.: 28 AF XY: 0.0000166 AC XY: 12 AN XY: 723630

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000698

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00000904

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000276 AC: 4 AN: 145134 Hom.: 0 Cov.: 32 AF XY: 0.0000285 AC XY: 2 AN XY: 70236

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000301

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000378

ExAC AF: 0.00000829 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 07, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	May 09, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 396 of the GALC protein (p.Arg396Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Krabbe Disease (PMID: 3362311, 9338580, 26795590, 27638592; Invitae). This variant is also known as R380W. ClinVar contains an entry for this variant (Variation ID: 456712). 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: 21876145, 24297913, 27638593). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.1186C>T (p.Arg396Trp) in GALC gene has been reported in compound heterozygous state in individuals affected with Krabbe disease (Tappino B. et al., 2010). Experimental studies have shown that this missense demonstrated less compactness and reduced number of intramolecular hydrogen bonds indicating loss of protein stability (D TK. et al., 2021). This variant is reported with the allele frequency (0.001%) in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar as a Pathogenic variant. The amino acid Arginine at position 396 is changed to a Tryptophan changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. For these reasons, this variant has been classified as Pathogenic. No significant reportable GALC variant was detected in the spouse. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 13, 2022	Variant summary: GALC c.1186C>T (p.Arg396Trp) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 59, central domain (IPR035394) of 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 1.6e-05 in 248096 control chromosomes (gnomAD). c.1186C>T has been reported in the literature in multiple individuals affected with Krabbe Disease (e.g. Wenger_1997, Tappino_2010, Orsini_2016, Krieg_2020, Bascou_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that this variant causes significant decrease of GALC activity (Saavedra-Martiz_2016). Seven ClinVar submitters have assessed the variant since 2014: 1 classified the variant as likely pathogenic and six pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000456712, PMID:9338580, PS1_S). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 21876145, 24297913, 27638593, PS3_M). A different missense change at the same codon has been reported to be associated with GALC related disorder (PMID:27779215,11151421, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.914, 3CNET: 0.917, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000016, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 20, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2023	Published functional studies demonstrate a damaging effect with reduced GALC activity (Saaverda-Matiz et al., 2016); Not observed at a significant frequency in large population cohorts (gnomAD); Also known as R380W using alternative nomenclature; This variant is associated with the following publications: (PMID: 3362311, 20886637, 23319190, 27638593, 27126738, 21876145, 24297913, 31707742, 32186243, 31240153, 9338580, 26795590, 27638592, 21824559, 33178108, 31589614) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.1	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.8	D;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.93
MutPred		0.83		Gain of catalytic residue at P397 (P = 0.0057);.;.;.;
MVP		1.0
MPC		0.60
ClinPred		0.98	D
GERP RS		0.91
Varity_R		0.56
gMVP		0.88

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

LitVar

Other links and lift over

dbSNP: rs770485731; hg19: chr14-88417068; COSMIC: COSV54331047; COSMIC: COSV54331047;