rs786204496
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000153.4(GALC):βc.1472delβ(p.Lys491ArgfsTer62) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,460,754 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes π: 0.000011 ( 0 hom. )
Consequence
GALC
NM_000153.4 frameshift
NM_000153.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.17
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 14-87947744-CT-C is Pathogenic according to our data. Variant chr14-87947744-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 188826.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.1472del | p.Lys491ArgfsTer62 | frameshift_variant | 13/17 | ENST00000261304.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GALC | ENST00000261304.7 | c.1472del | p.Lys491ArgfsTer62 | frameshift_variant | 13/17 | 1 | NM_000153.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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GnomAD3 exomes AF: 0.0000562 AC: 14AN: 248960Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135060
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GnomAD4 exome AF: 0.0000110 AC: 16AN: 1460754Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726728
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Galactosylceramide beta-galactosidase deficiency Pathogenic:4Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 19, 2021 | Variant summary: GALC c.1472delA (p.Lys491ArgfsX62) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 5.6e-05 in 248960 control chromosomes. c.1472delA has been reported in the literature in individuals affected with Krabbe Disease (e.g. Wenger_1997, Beltran-Quintero_2019). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence indicating that the variant results in reduced GALC activity when expressed in-vitro (e.g. Saavedra-Martiz_2016). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | literature only | Counsyl | Jun 10, 2014 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 23, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change creates a premature translational stop signal (p.Lys491Argfs*62) in the GALC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GALC are known to be pathogenic (PMID: 7437911, 9272171, 16607461). This variant is present in population databases (rs771489305, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with GALC-related conditions (PMID: 9338580). ClinVar contains an entry for this variant (Variation ID: 188826). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 10, 2022 | Functional studies of this variant showed only residual GALC activity (Saavedra-Matiz et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27638593, 9338580) - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at