rs1418694289
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000153.4(GALC):āc.1895T>Cā(p.Leu632Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,608,808 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 ). Synonymous variant affecting the same amino acid position (i.e. L632L) has been classified as Likely benign.
Frequency
Consequence
NM_000153.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GALC | NM_000153.4 | c.1895T>C | p.Leu632Pro | missense_variant | 16/17 | ENST00000261304.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GALC | ENST00000261304.7 | c.1895T>C | p.Leu632Pro | missense_variant | 16/17 | 1 | NM_000153.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151942Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248836Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135016
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1456866Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 725090
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151942Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74200
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 | Jul 28, 2023 | Variant summary: GALC c.1895T>C (p.Leu632Pro) 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 allele was found at a frequency of 4e-06 in 248836 control chromosomes. c.1895T>C has been reported in the literature in at least two individuals affected with Krabbe Disease (e.g. Orsini_2016, Beltran-Quintero_2019). One individual was found only to be heterozygous, and the other individual was found to be compound heterozygous with a pathogenic variant (p.Arg210*). These data suggest that the variant may be associated with disease, but do not allow any definitive conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function (Saavedra-Matiz_2016). The most pronounced variant effect results in 10%-<30% of normal activity. The following publications have been ascertained in the context of this evaluation (PMID: 30777126, 26795590, 27638593). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has 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 | May 23, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at