rs750531880
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000404.4(GLB1):c.902C>T(p.Ala301Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,060 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A301T) 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 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLB1 | NM_000404.4 | c.902C>T | p.Ala301Val | missense_variant | 8/16 | ENST00000307363.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLB1 | ENST00000307363.10 | c.902C>T | p.Ala301Val | missense_variant | 8/16 | 1 | NM_000404.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000802 AC: 2AN: 249468Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135330
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461888Hom.: 0 Cov.: 34 AF XY: 0.0000165 AC XY: 12AN XY: 727246
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74346
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 21, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 02, 2017 | The c.902 C>T pathogenic variant in the GLB1 gene has been reported previously with another GLB1 variant in multiple unrelated individuals with GM1-gangliosidosis (Santamaria et al., 2006; Yang et al., 2010; Hofer et al., 2010). Functional studies have shown that the c.902 C>T variant is associated with significantly reduced beta-galactosidase activity (Yang et al., 2010). The c.902 C>T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In-silico splice prediction models predict that c.902 C>T may create a cryptic splice donor site in exon 8, which may cause abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of the c.902 C>T change in this individual is unknown. If c.902 C>T does not alter splicing, it will result in the A301V missense change. The A301V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret c.902 C>T as a pathogenic variant. - |
GLB1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 04, 2023 | The GLB1 c.902C>T variant is predicted to result in the amino acid substitution p.Ala301Val. This variant has been reported in the compound heterozygous state in individuals with Gangliosidosis GM1, including one sibling pair (Hofer et al. 2010. Table 1 PubMed ID: 20175788; Yang et al. 2010. PubMed ID: 20920281; Arash-Kaps et al. 2019. Table III PubMed ID: 31761138; King et al. 2020. Table 1 PubMed ID: 33240792; Santamaria et al. 2006. PubMed ID: 16941474). This variant has been reported to affect splicing and to significantly reduce enzyme activity in vitro compared to control (Santamaria et al. 2006. PubMed ID: 16941474; Hofer et al. 2010. Table 3 PubMed ID: 20175788; Yang et al. 2010. PubMed ID: 20920281). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-33093387-G-A). Taken together, this variant is interpreted as pathogenic. - |
Mucopolysaccharidosis, MPS-IV-B Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Oct 23, 2017 | - - |
GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 24, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 301 of the GLB1 protein (p.Ala301Val). This variant is present in population databases (rs750531880, gnomAD 0.002%). This missense change has been observed in individual(s) with GM1 gangliosidosis (PMID: 16941474, 20175788, 20409738, 20920281). This variant is also known as r.901_914del. ClinVar contains an entry for this variant (Variation ID: 381567). 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: 16941474, 20175788). 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. - |
GM1 gangliosidosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 29, 2023 | Variant summary: GLB1 c.902C>T (p.Ala301Val) results in a non-conservative amino acid change located in the Glycoside hydrolase 35, catalytic domain (IPR031330) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic 5' splicing donor site, and one predicts the variant strengthens this site. At least one publication reports experimental evidence that this variant affects mRNA splicing, finding that inhibition of nonsense-mediated decay in a patient with the variant allowed detection of the transcript, which contains a deletion of 14 nucleotides at the 3' end of exon 8 (Santamaria_2006). The variant allele was found at a frequency of 8e-06 in 249468 control chromosomes (gnomAD). c.902C>T has been reported in the literature in individuals affected with GM1 Gangliosidosis (Yang_2010, Hofer_2010, Santamaria_2006, Arash-Kaps_2019, King_2020), and some were reported as compound heterozygous with other pathogenic variants. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding no residual enzymatic activity in transfected cells (Yang_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20920281, 20175788, 16941474, 31761138, 33240792). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at