chr3-33016743-C-T
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000404.4(GLB1):c.1445G>A(p.Arg482His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,990 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. R482C) 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 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLB1 | NM_000404.4 | c.1445G>A | p.Arg482His | missense_variant | 14/16 | ENST00000307363.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLB1 | ENST00000307363.10 | c.1445G>A | p.Arg482His | missense_variant | 14/16 | 1 | NM_000404.4 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249584Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135410
GnomAD4 exome AF: 0.0000192 AC: 28AN: 1461818Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16AN XY: 727210
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74332
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-IV-B Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1993 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Feb 13, 2018 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 14, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 07, 2023 | Published functional studies demonstrate that this variant results in almost no residual enzymatic activity (Caciotti et al., 2005); This variant is associated with the following publications: (PMID: 15714521, 15943552, 7586649, 1487238, 11511921, 1928092, 16538002, 25936995, 22128166, 8500799, 21520340, 18353697, 15365997, 17221873, 21497194, 10737981, 34426522, 32779865) - |
Infantile GM1 gangliosidosis Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 19, 2020 | Based on the classification scheme VCGS_Germline_v1.3.3, 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 Type I GM1-gangliosidosis (MIM#230500). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 3 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ß domain 1 (PMID: 25936995). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. At least 10 type I GM1-gangliosidosis (MIM#230500) patients have been reported to be either homozygous or compound heterozygous for this variant (ClinVar; PMID: 10737981, 15943552, 15714521, 17221873, 25936995). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000404.3:c.1480-2A>G) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (SA pathology Lab ID: FAMCa 2473751)/ (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1993 | - - |
GM1 gangliosidosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 09, 2016 | Variant summary: The GLB1 c.1445G>A (p.Arg482His) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/120872 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic GLB1 variant (0.0020412). This variant has been reported in multiple patients with Morquio B disease and Gm1-gangliosidosis. Functional testing showed that variant allele with non-detectable enzyme activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 482 of the GLB1 protein (p.Arg482His). This variant is present in population databases (rs72555391, gnomAD 0.006%). This missense change has been observed in individual(s) with GLB1-related conditions (PMID: 1928092, 15943552). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 932). 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: 15943552). For these reasons, this variant has been classified as Pathogenic. - |
Mucopolysaccharidosis, MPS-IV-B;C0268271:Infantile GM1 gangliosidosis;C0268272:GM1 gangliosidosis type 2;C0268273:GM1 gangliosidosis type 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 20, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at