rs377274761
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000153.4(GALC):c.850G>A(p.Gly284Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,613,552 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G284D) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000153.4 missense
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GALC | NM_000153.4 | c.850G>A | p.Gly284Ser | missense_variant | 8/17 | ENST00000261304.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GALC | ENST00000261304.7 | c.850G>A | p.Gly284Ser | missense_variant | 8/17 | 1 | NM_000153.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 151924Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000802 AC: 2AN: 249278Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135226
GnomAD4 exome AF: 0.0000404 AC: 59AN: 1461628Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30AN XY: 727118
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 151924Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74188
ClinVar
Submissions by phenotype
Galactosylceramide beta-galactosidase deficiency Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 284 of the GALC protein (p.Gly284Ser). This variant is present in population databases (rs377274761, gnomAD 0.002%). This missense change has been observed in individual(s) with Krabbe disease or its clinical features (PMID: 8940268, 22520351, 29286531). It has also been observed to segregate with disease in related individuals. This variant is also known as p.G268S. ClinVar contains an entry for this variant (Variation ID: 374024). 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. Experimental studies have shown that this missense change affects GALC function (PMID: 8940268, 27638593). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 08, 2016 | Variant summary: The GALC c.850G>A (p.Gly284Ser) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/120666 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic GALC variant (0.0022361). This variant has been reported in multiple affected individuals with evidence of co-segregation. Functional assay showed variant with 5% of WT activity (De Gasperi et al 1996). Taken together, this variant is classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jul 27, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Likely pathogenic. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | May 25, 2017 | - - |
Amblyopia;C0006157:Breech presentation;C0015934:Fetal growth restriction;C0018989:Hemiparesis;C0023520:Leukodystrophy;C0028738:Nystagmus;C0036572:Seizure;C0038220:Status epilepticus;C0038379:Strabismus;C0151611:EEG abnormality;C0158986:Neonatal hypoglycemia;C0235991:Small for gestational age;C0476403:EMG abnormality;C0557874:Global developmental delay;C1836830:Developmental regression;C1836843:Loss of ambulation;C1839364:Progressive visual loss;C3278204:Dysmyelinating leukodystrophy;C4025609:EMG: axonal abnormality Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Oct 28, 2015 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 14, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at