rs776327443
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_ModeratePM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000404.4(GLB1):c.1646C>T(p.Pro549Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,058 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 Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P549S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000404.4 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 |
---|---|---|---|---|---|---|---|
GLB1 | NM_000404.4 | c.1646C>T | p.Pro549Leu | missense_variant | 15/16 | ENST00000307363.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLB1 | ENST00000307363.10 | c.1646C>T | p.Pro549Leu | missense_variant | 15/16 | 1 | NM_000404.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152166Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000201 AC: 5AN: 248816Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135066
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461892Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7AN XY: 727246
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74334
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-IV-B Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Mar 16, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 09, 2023 | Variant summary: GLB1 c.1646C>T (p.Pro549Leu) results in a non-conservative amino acid change located in the Beta-galactosidase jelly roll domain of 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 2e-05 in 248816 control chromosomes. c.1646C>T has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IVB (Morquio Syndrome B). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Celtikci_2012). The following publications have been ascertained in the context of this evaluation (PMID: 17221873, 22234367, 17309651). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 08, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 27, 2017 | The P549L variant is classified as a severe GLB1 variant associated with type I (infantile) GM1-gangliosidosis phenotype (Santamaria et al. 2007; Caciotti et al. 2007; Higaki et al. 2011; Celtikçi et al. 2012). The P549L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P549L variant is a semi-conservative amino acid substitution that occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, P549 is located in the galactose-binding domain-like structure of the β-galactosidase protein. Variants in this region are expected to be severe as they likely result in changes to the structure of the enzyme's active site and/or substrate binding site (Celtikçi et al. 2012). In summary, we interpret P549L as pathogenic. - |
GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 06, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 549 of the GLB1 protein (p.Pro549Leu). This variant is present in population databases (rs776327443, gnomAD 0.01%). This missense change has been observed in individual(s) with GM1 gangliosidosis (PMID: 17221873, 17309651, 22234367). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 426185). 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 GLB1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GLB1 function (PMID: 21520340). For these reasons, this variant has been classified as Pathogenic. - |
Infantile GM1 gangliosidosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Jan 12, 2022 | PM2, PM3, PP2, PP3, PP5 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at