rs886042057

Positions:

• chr14-87992970-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The ENST00000261304.7(GALC):​c.195G>C​(p.Gly65=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,520,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G65G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: GALC ENST00000261304.7 splice_region, synonymous
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.10

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-87992970-C-G is Pathogenic according to our data. Variant chr14-87992970-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 280959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALC	NM_000153.4	c.195G>C	p.Gly65=	splice_region_variant, synonymous_variant	1/17	ENST00000261304.7	NP_000144.2
GALC	NM_001201401.2	c.195G>C	p.Gly65=	splice_region_variant, synonymous_variant	1/16		NP_001188330.1
GALC	NM_001201402.2	c.117+413G>C		intron_variant			NP_001188331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7	c.195G>C	p.Gly65=	splice_region_variant, synonymous_variant	1/17	1	NM_000153.4	ENSP00000261304	P1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

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

GnomAD4 exome AF: 0.00000439 AC: 6 AN: 1367970 Hom.: 0 Cov.: 33 AF XY: 0.00000444 AC XY: 3 AN XY: 676338

Gnomad4 AFR exome AF: 0.000216

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74462

Gnomad4 AFR AF: 0.000361

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000117

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Mar 13, 2020	This variant affects the splice donor site of exon 1 and is therefore predicted to interfere with splicing and result in loss of normal protein function. This variant has been previously reported in individuals with late onset Krabbe's disease as a compound heterozygous change in two related individuals (PMID: 9005874, 8940268), the compound homozygous state in one individual (PMID: 23197103), and in one individual with no second variant identified (PMID: 23197103). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.006% (2/31320) and thus is presumed to be rare. Multiple splice prediction tools suggest this variant is likely to interfere with normal splicing. This variant is present in the ClinVar database (Variation ID: 280959). Functional studies support a damaging effect of this variant on splicing (PMID: 8940268). . Based on the available evidence, the c.195G>C (p.Gly65=) variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 26, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 02, 2023	This sequence change affects codon 65 of the GALC mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GALC protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (no rsID available, gnomAD 0.02%). This variant has been observed in individual(s) with Krabbe disease (PMID: 8940268, 9005874, 23197103). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 280959). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in abnormal splicing and introduces a premature termination codon (PMID: 8940268). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 18, 2022	Variant summary: GALC c.195G>C (p.Gly65Gly) alters a conserved nucleotide located as the last nucleotide of exon 1 adjacent to the canonical intron 1 splice donor site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' splicing donor site. Two predict the variant weakens the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in first 126 bases of intron 1 inserted in-frame between nucleotides 195 and 196 (legacy nucleotides 147 and 148) (exactly at the junction of exons 1 and 2), because of the activation of a cryptic splice site (De Gasperi_1996). The variant was absent in 125252 control chromosomes. c.195G>C has been reported in the literature in individuals affected with slowly progressive/late onset Krabbe Disease (example, De Gasperi_1996, Bernardini_1997, Debs_2013). These data indicate that the variant is likely to be associated with disease. Five 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 06, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.49		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs886042057; hg19: chr14-88459314;