rs1555383679
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000153.4(GALC):c.433dupA(p.Thr145AsnfsTer43) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000281 in 1,425,992 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000153.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GALC | NM_000153.4 | c.433dupA | p.Thr145AsnfsTer43 | frameshift_variant | Exon 4 of 17 | ENST00000261304.7 | NP_000144.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000281 AC: 4AN: 1425992Hom.: 0 Cov.: 27 AF XY: 0.00000281 AC XY: 2AN XY: 711584
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Galactosylceramide beta-galactosidase deficiency Pathogenic:4
This sequence change creates a premature translational stop signal (p.Thr145Asnfs*43) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Krabbe disease (PMID: 22115770). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.384_385insA. ClinVar contains an entry for this variant (Variation ID: 553285). For these reasons, this variant has been classified as Pathogenic. -
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Variant summary: GALC c.433dupA (p.Thr145AsnfsX43) 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 (e.g. c.628A>T (p.Arg210X), c.1814dupA (p.Tyr605X)). The variant was absent in 245842 control chromosomes (gnomAD). The c.433dupA has been reported in the literature in an individual affected with Krabbe Disease (Puckett 2012). This publication also reported evidence evaluating an impact on protein function, demonstrating a severely decreased galactocerebrosidase activity measured in leukocytes (<10% of normal activity). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at