rs1555383892
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The ENST00000261304.7(GALC):c.203C>T(p.Ser68Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,374 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). Synonymous variant affecting the same amino acid position (i.e. S68S) has been classified as Likely benign.
Frequency
Consequence
ENST00000261304.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GALC | NM_000153.4 | c.203C>T | p.Ser68Phe | missense_variant | 2/17 | ENST00000261304.7 | NP_000144.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GALC | ENST00000261304.7 | c.203C>T | p.Ser68Phe | missense_variant | 2/17 | 1 | NM_000153.4 | ENSP00000261304 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1458374Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 725792
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Galactosylceramide beta-galactosidase deficiency Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 03, 2022 | The p.Ser68Phe variant in GALC has been reported in the compound heterozygote state in at least 3 individuals with Krabbe disease (Fu 1999 PMID: 10234611, Madsen 2019 PMID: 31240153, Pushkov 2020 doi: 10.17816/2686-8997-2020-1-01-21-28). It has been reported in ClinVar (Variation ID 552834) and was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Krabbe disease. ACMG/AMP Criteria applied: PM2_supporting, PM3_strong, PP3. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jul 11, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 19, 2022 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects GALC function (PMID: 10234611). 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: 552834). This variant is also known as p.S52F. This missense change has been observed in individual(s) with Krabbe disease (PMID: 10234611, 24252386). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 68 of the GALC protein (p.Ser68Phe). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at