3-33072587-G-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PM5PP3_StrongPP5_Moderate
The NM_000404.4(GLB1):āc.202C>Gā(p.Arg68Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,664 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 (ā ). 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 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLB1 | NM_000404.4 | c.202C>G | p.Arg68Gly | missense_variant | 2/16 | ENST00000307363.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLB1 | ENST00000307363.10 | c.202C>G | p.Arg68Gly | missense_variant | 2/16 | 1 | NM_000404.4 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461664Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727128
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 20, 2020 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg68 amino acid residue in GLB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12644936, 25936995). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals with GLB1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 68 of the GLB1 protein (p.Arg68Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.