rs756878418
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.175C>T(p.Arg59Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,613,976 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. R59H) 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GLB1 | NM_000404.4 | c.175C>T | p.Arg59Cys | missense_variant | 2/16 | ENST00000307363.10 | NP_000395.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GLB1 | ENST00000307363.10 | c.175C>T | p.Arg59Cys | missense_variant | 2/16 | 1 | NM_000404.4 | ENSP00000306920.4 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152164Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000481 AC: 12AN: 249480Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135348
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461812Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 727206
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74320
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 03, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Mucopolysaccharidosis, MPS-IV-B;C0268271:Infantile GM1 gangliosidosis;C0268272:GM1 gangliosidosis type 2;C0268273:GM1 gangliosidosis type 3 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Sep 11, 2017 | - - |
GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 02, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 59 of the GLB1 protein (p.Arg59Cys). This variant is present in population databases (rs756878418, gnomAD 0.04%). This missense change has been observed in individual(s) with GM1 gangliosidosis (PMID: 15714521, 16941474, 17309651). ClinVar contains an entry for this variant (Variation ID: 496895). 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: 15714521). This variant disrupts the p.Arg59 amino acid residue in GLB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10338095, 16941474, 17309651, 17664528). 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. - |
Infantile GM1 gangliosidosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jul 27, 2021 | ACMG classification criteria: PS4 moderate, PM2 moderate, PM3 strong, PP3 supporting, PP4 supporting - |
GM1 gangliosidosis type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at