14-87984398-A-G
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_000153.4(GALC):āc.578T>Cā(p.Ile193Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,020 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000153.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GALC | NM_000153.4 | c.578T>C | p.Ile193Thr | missense_variant | 5/17 | ENST00000261304.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GALC | ENST00000261304.7 | c.578T>C | p.Ile193Thr | missense_variant | 5/17 | 1 | NM_000153.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461020Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726806
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Galactosylceramide beta-galactosidase deficiency Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 02, 2022 | Variant summary: GALC c.578T>C (p.Ile193Thr) 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 was absent in 249294 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.578T>C has been reported in the literature in individuals affected with Krabbe Disease from the Russian population (e.g. Zakharova_2008, Nagornov_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) have cited the variant; one submitter classified the variant as likely pathogenic, and the other classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 02, 2021 | This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GALC protein function. ClinVar contains an entry for this variant (Variation ID: 522714). This variant is also known as p.Ile177Thr. This missense change has been observed in individual(s) with Krabbe disease (PMID: 18846620). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 193 of the GALC protein (p.Ile193Thr). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at