rs72555370
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1_ModeratePM2PM5PP3_ModeratePP5_Very_Strong
The NM_000404.4(GLB1):c.202C>T(p.Arg68Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,844 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. R68L) 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 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLB1 | NM_000404.4 | c.202C>T | p.Arg68Trp | missense_variant | 2/16 | ENST00000307363.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLB1 | ENST00000307363.10 | c.202C>T | p.Arg68Trp | missense_variant | 2/16 | 1 | NM_000404.4 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000281 AC: 7AN: 249454Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135338
GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461664Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16AN XY: 727128
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74344
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 10, 2023 | Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 12644936); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33737400, 31367523, 21497194, 12644936, 29352662, 25936995, 31761138) - |
GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 11, 2023 | This variant disrupts the p.Arg68 amino acid residue in GLB1. Other variant(s) that disrupt this residue have been observed in individuals with GLB1-related conditions (PMID: 19472408, 29439846), which suggests that this may be a clinically significant amino acid residue. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 68 of the GLB1 protein (p.Arg68Trp). This variant is present in population databases (rs72555370, gnomAD 0.01%). This missense change has been observed in individual(s) with GM1 gangliosidosis (PMID: 12644936, 25936995). ClinVar contains an entry for this variant (Variation ID: 944). 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. Experimental studies have shown that this missense change affects GLB1 function (PMID: 12644936). For these reasons, this variant has been classified as Pathogenic. - |
Infantile GM1 gangliosidosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota | Aug 29, 2017 | - - |
GM1 gangliosidosis type 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2003 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at