rs72555360
Positions:
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.601C>T(p.Arg201Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000731 in 1,614,140 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 (★★). 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. R201H) has been classified as Likely pathogenic.
Frequency
Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000072 ( 0 hom. )
Consequence
GLB1
NM_000404.4 missense
NM_000404.4 missense
Scores
11
5
2
Clinical Significance
Conservation
PhyloP100: 7.65
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 20 ACMG points.
PS1
Transcript NM_000404.4 (GLB1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
In a disulfide_bond (size 35) in uniprot entity BGAL_HUMAN there are 15 pathogenic changes around while only 1 benign (94%) in NM_000404.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.948
PP5
Variant 3-33058221-G-A is Pathogenic according to our data. Variant chr3-33058221-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-33058221-G-A is described in Lovd as [Pathogenic]. Variant chr3-33058221-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| GLB1 | NM_000404.4 | c.601C>T | p.Arg201Cys | missense_variant | 6/16 | ENST00000307363.10 | NP_000395.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| GLB1 | ENST00000307363.10 | c.601C>T | p.Arg201Cys | missense_variant | 6/16 | 1 | NM_000404.4 | ENSP00000306920 | P2 |
Frequencies
GnomAD3 genomes 0.0000854 AC: 13AN: 152162Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000442 AC: 11AN: 249004Hom.: 0 AF XY: 0.0000592 AC XY: 8AN XY: 135164
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GnomAD4 exome AF: 0.0000718 AC: 105AN: 1461860Hom.: 0 Cov.: 32 AF XY: 0.0000715 AC XY: 52AN XY: 727232
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GnomAD4 genome 0.0000854 AC: 13AN: 152280Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74452
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:14Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
GM1 gangliosidosis type 2 Pathogenic:4Other:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2003 | - - |
| Pathogenic, criteria provided, single submitter | research | Dr. Faghihi's Medical Genetic Center | Jan 20, 2017 | Four cases affected by GM1 gangliosidosis type II from three consanguineous families showed a homozygote missense mutation in GLB1 gene (c. 601 G> A, p.R201C). Their clinical findings were as follow: Family I, Patient I: A 6.5-year-old girl was referred to the Pediatric Neurology Department in the Mofid Children Hospital, Tehran, Iran due to progressive ataxia and neurodevelopmental regression. She was born from a consanguineous marriage (first-degree cousins) with uneventful birth history. She had normal neurodevelopmental milestones up to the age of three years when she developed progressive ataxia. She gradually lost her lingual and motor skills and became wheelchair-dependent by the age of 5 years. Although she was reported to have normal intellectual abilities, her mental abilities decreased over the course of disease. Detailed neurological exam was performed in the first admission and in the subsequent visits, which revealed neurodevelopmental regression, reduction of age-related intellectual abilities and nystagmus. The “Fix and Follow test†of moving objects was not normal and she gradually lost her vision. Two magnetic resonance imaging (MRI) (in the third and fourth) assessments revealed minor signal changes in the periventricular white matter without any progression (Figure 1a and 1b). Ophthalmologic study did not show any pathologic signs and all metabolic studies were reported in normal range. Electroencephalography (EEG), Visual Evoked Potential (VEP) and Electroretinography (ERG) were normal.. Regarding her family history, 4 members in her mother’s family died due to similar clinical presentations. Family II, Patient II & III: The family had two affected individuals who were referred to the Pediatric Neurology Department in the Mofid Children Hospital, Tehran, Iran due to neurodevelopmental regression. These two siblings, a 9-year-old boy and a 4-year-old girl, had normal developmental milestones up to the age of 3 years. The boy showed progressive ataxia, dystonia and mental decline. All metabolic studies and routine laboratory data were in normal ranges. MRI study showed mild cerebellar atrophy with mild signal changes in the periventricular white matter (Figure 2). The affected girl had similar symptoms with loss of her acquired motor and lingual abilities after the age of 3 years as well as progressive ataxia, speech problem and neurodevelopmental regression. The parents are first-degree cousins who have one unaffected child and positive history of multiple deceased individuals with similar clinical presentation in their extended family. Family III, Patient IV: The patient is an 8-years old girl, who is already bed-ridden and living in the same village as the family II. She was reported to have similar findings to the family II which include progressive ataxia, neurodevelopmental regression, loss of speech and mental decline started around the age of 3 years. Her parents are first-degree cousins and have history of unexplained death of children in their extended families from both sides. - |
| not provided, no classification provided | phenotyping only | GenomeConnect - GM1 | - | Variant interpreted as Pathogenic and reported on 08-11-2016 by lab or GTR ID Hudson Alpha. GenomeConnect - GM1 assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Jul 14, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Oct 30, 2016 | - - |
not provided Pathogenic:3
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 30, 2023 | Functional studies found that R201C is associated with approximately 3-12% residual beta-galactosidase activity (PMID: 12644936, 1907800, 19472408); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20409738, 20826101, 24156116, 16626397, 10737981, 16617000, 16538002, 17994547, 18937943, 15744523, 21504867, 8068159, 28716012, 29439846, 8112731, 33737400, 15943552, 22436580, 11511921, 22033734, 21144509, 20175788, 25600812, 23151865, 17664528, 18202827, 16763919, 25443580, 24024947, 23337983, 21520340, 19472408, 22784478, 21517827, 25151393, 18546276, 16314480, 23820649, 14676316, 19812739, 1928092, 25925601, 28554332, 30581635, 25557439, 26646981, 1909089, 33859490, 35029890, 34816592, 33980489, 12644936, 1907800) - |
Infantile GM1 gangliosidosis Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 18, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Oct 30, 2016 | - - |
GLB1-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 11, 2024 | The GLB1 c.601C>T variant is predicted to result in the amino acid substitution p.Arg201Cys. This variant was reported to be causative for GM1 Gangliosidosis (Yoshida et. al. 1991. PubMed ID: 1907800; Karimzadeh et al. 2017. PubMed ID: 28716012). Pathogenic variants in GLB1 have been associated with autosomal recessive GM1-gangliosidosis, type I (OMIM #230500), autosomal recessive GM1-gangliosidosis, type II (OMIM #230600), autosomal recessive GM1-gangliosidosis, type III (OMIM #230650), and autosomal recessive Mucopolysaccharidosis type IVB, Morquio (OMIM #253010). This variant is reported in 0.0089% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. - |
GM1 gangliosidosis type 3 Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Oct 30, 2016 | - - |
Mucopolysaccharidosis, MPS-IV-B Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Oct 30, 2016 | - - |
GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 01, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 201 of the GLB1 protein (p.Arg201Cys). This variant is present in population databases (rs72555360, gnomAD 0.009%). This missense change has been observed in individual(s) with GLB1-related conditions (PMID: 1907800, 25443580, 28554332, 28716012, 29439846). ClinVar contains an entry for this variant (Variation ID: 925). 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: 16617000). This variant disrupts the p.Arg201 amino acid residue in GLB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9203065, 11511921, 17309651, 20175788, 23430499). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
GM1 gangliosidosis Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The GLB1 c.601C>T (p.Arg201Cys) missense variant has been reported in four studies in which it is found in a total of eight individuals with GM1 gangliosidosis including in one in a homozygous state, in three in a compound heterozygous state, and in four in a heterozygous state where a second variant was not identified (Yoshida et al. 1991; Nishimoto et al 1991; Caciotti et al 2003; Takenouchi et al 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00005 in the European (non-Finnish) population of the Exome Aggregation Consortium. Caciotti et al. (2003) investigated the functional impact of GLB1 variants through expression studies in COS-1 cells and demonstrated that the p.Arg201Cys variant resulted in 12.9% of wild type activity. Based on the evidence, the p.Arg201Cys variant is classified as likely pathogenic for GM1 gangliosidosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
.;.;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;T;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
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