rs72555359
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000404.4(GLB1):c.1369C>T(p.Arg457Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000805 in 1,613,910 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
GLB1
NM_000404.4 stop_gained
NM_000404.4 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 3.97
Genes affected
GLB1 (HGNC:4298): (galactosidase beta 1) This gene encodes a member of the glycosyl hydrolase 35 family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature lysosomal enzyme. This enzyme catalyzes the hydrolysis of a terminal beta-linked galactose residue from ganglioside substrates and other glycoconjugates. Mutations in this gene may result in GM1-gangliosidosis and Morquio B syndrome. [provided by RefSeq, Nov 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 3-33016819-G-A is Pathogenic according to our data. Variant chr3-33016819-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLB1 | NM_000404.4 | c.1369C>T | p.Arg457Ter | stop_gained | 14/16 | ENST00000307363.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLB1 | ENST00000307363.10 | c.1369C>T | p.Arg457Ter | stop_gained | 14/16 | 1 | NM_000404.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152146Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249532Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135374
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GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461764Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727184
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Infantile GM1 gangliosidosis Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 1991 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 05, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2023 | GLB1: PM3:Strong, PVS1:Strong, PM2, PP4 - |
GM1 gangliosidosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 06, 2020 | Variant summary: GLB1 c.1369C>T (p.Arg457X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.6e-05 in 249532 control chromosomes (gnomAD). c.1369C>T has been reported in the literature in individuals affected with GM1 gangliosidosis (e.g. Nishimoto_1991, Santamaria_2007, Matalonga_2015). These data indicate that the variant is likely to be associated with disease. Cells expressing the variant were shown to have indetectable levels of acid beta-galactosidase enzymatic activity (Nishimoto_1991). One Clin Var submitter (evaluation after 2014 ) cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 22, 2023 | This sequence change creates a premature translational stop signal (p.Arg457*) in the GLB1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GLB1 are known to be pathogenic (PMID: 18524657). This variant is present in population databases (rs72555359, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with GM1 gangliosidosis (PMID: 1909089, 25936995, 28976722, 30548430). ClinVar contains an entry for this variant (Variation ID: 924). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 | Counsyl | May 19, 2017 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at