3-33058250-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5
The NM_000404.4(GLB1):c.572G>A(p.Ser191Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,862 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S191I) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000404.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLB1 | NM_000404.4 | c.572G>A | p.Ser191Asn | missense_variant | 6/16 | ENST00000307363.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLB1 | ENST00000307363.10 | c.572G>A | p.Ser191Asn | missense_variant | 6/16 | 1 | NM_000404.4 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461862Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727232
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 191 of the GLB1 protein (p.Ser191Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GM1-gangliosidosis (PMID: 21497194, 32779865). ClinVar contains an entry for this variant (Variation ID: 549962). 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%. For these reasons, this variant has been classified as Pathogenic. - |
Mucopolysaccharidosis, MPS-IV-B;C0268271:Infantile GM1 gangliosidosis;C0268272:GM1 gangliosidosis type 2;C0268273:GM1 gangliosidosis type 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 15, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at