rs1555383882
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000153.4(GALC):āc.251A>Gā(p.Asp84Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,084 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 Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D84N) has been classified as Uncertain significance.
Frequency
Consequence
NM_000153.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GALC | NM_000153.4 | c.251A>G | p.Asp84Gly | missense_variant | 2/17 | ENST00000261304.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GALC | ENST00000261304.7 | c.251A>G | p.Asp84Gly | missense_variant | 2/17 | 1 | NM_000153.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152084Hom.: 0 Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1451210Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 722826
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152084Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74284
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 10, 2023 | Variant summary: GALC c.251A>G (p.Asp84Gly) results in a non-conservative amino acid change located in the catalytic domain (IPR049161) of 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 249240 control chromosomes (gnomAD). c.251A>G has been reported in the literature in at least one individual identified through newborn screening as being at low or moderate risk of developing Krabbe disease based on GALC activity levels, who harbored a pathogenic variant in trans (e.g., Orsini_2016). This report does not provide unequivocal conclusions about association of the variant with Krabbe Disease. At least one publication reports experimental evidence evaluating an impact on protein function (e.g., Saavedra-Martiz_2016). The most pronounced variant effect results in <10% of normal GALC activity. The following publications have been ascertained in the context of this evaluation (PMID: 26795590, 27638593). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Galactosylceramide beta-galactosidase deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 10, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 28, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at