rs387906952
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000153.4(GALC):c.1630G>A(p.Asp544Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000932 in 1,609,020 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D544D) has been classified as Likely benign.
Frequency
Consequence
NM_000153.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GALC | NM_000153.4 | c.1630G>A | p.Asp544Asn | missense_variant | 14/17 | ENST00000261304.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GALC | ENST00000261304.7 | c.1630G>A | p.Asp544Asn | missense_variant | 14/17 | 1 | NM_000153.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151982Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000804 AC: 2AN: 248886Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135022
GnomAD4 exome AF: 0.00000892 AC: 13AN: 1457038Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10AN XY: 725176
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151982Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74222
ClinVar
Submissions by phenotype
Galactosylceramide beta-galactosidase deficiency Pathogenic:7
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jul 24, 2022 | ACMG classification criteria: PS3 supporting, PS4 supporting, PM2 moderated, PM3 supporting, PP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Krabbe disease (MIM#245200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (2 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has previous evidence of pathogenicity in unrelated individuals. This variant is found at high frequency in affected individuals from a specific region, likely representing a founder effect (PMID: 8786069, 12699861). (SP) 0901 - This variant has strong evidence for segregation with disease. Rafi et al identified this variant in six homozygous affected individuals and seven obligate heterozygotes from an inbred population (PMID: 8786069). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional assays in cell lines have shown this variant to result in reduced enzyme activity, protein instability, impaired trafficking, and hyperglycosylation of the GALC protein (PMID: 20410102, 26865610). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2010 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 15, 2022 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 544 of the GALC protein (p.Asp544Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with the infantile Krabbe disease (PMID: 8786069, 12699861). This variant is also known as c.1582G>A, p.D528N. ClinVar contains an entry for this variant (Variation ID: 30614). 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: 26865610). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Jul 20, 2024 | This patient was heterozygous of two known very rare variants, c.1630G>A and c.658C>T, in the GALC gene. The c.658C>T variant is predicted to result in premature protein termination (p.Arg220Ter). These variants have been reported for their pathogenicity in ClinVar. Both variants were segregated within the family using Sanger sequencing. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 26, 2017 | - - |
not provided Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Aug 06, 2019 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 14, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at