chr14-87984398-A-G

Variant names:

• chr14-87984398-A-G
• rs1555383498
• NM_000153.4:c.578T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_000153.4(GALC):​c.578T>C​(p.Ile193Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,020 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GALC NM_000153.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.29
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000153.4
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.938
• PP5: Variant 14-87984398-A-G is Pathogenic according to our data. Variant chr14-87984398-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 522714.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALC	NM_000153.4	c.578T>C	p.Ile193Thr	missense_variant	Exon 5 of 17	ENST00000261304.7	NP_000144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7	c.578T>C	p.Ile193Thr	missense_variant	Exon 5 of 17	1	NM_000153.4	ENSP00000261304.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461020 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726806

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111286

Other (OTH) AF: 0.0000166 AC: 1 AN: 60366

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Pathogenic:2 Uncertain:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 193 of the GALC protein (p.Ile193Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Krabbe disease (PMID: 18846620). This variant is also known as p.Ile177Thr. ClinVar contains an entry for this variant (Variation ID: 522714). 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%. 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. -

Dec 02, 2022

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GALC c.578T>C (p.Ile193Thr) 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 was absent in 249294 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.578T>C has been reported in the literature in individuals affected with Krabbe Disease from the Russian population (e.g. Zakharova_2008, Nagornov_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) have cited the variant; one submitter classified the variant as likely pathogenic, and the other classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;.;.;.
PhyloP100		9.3
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.99	D;D;D;.
Vest4		0.83
MutPred		0.72		Gain of catalytic residue at L188 (P = 0.0116);.;.;.;
MVP		1.0
MPC		0.32
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.53
gMVP		0.97
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555383498; hg19: chr14-88450742;