rs72555373
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate
The NM_000404.4(GLB1):āc.1771T>Cā(p.Tyr591His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,968 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. Y591C) 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.1771T>C | p.Tyr591His | missense_variant | 16/16 | ENST00000307363.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLB1 | ENST00000307363.10 | c.1771T>C | p.Tyr591His | missense_variant | 16/16 | 1 | NM_000404.4 | P2 | |
GLB1 | ENST00000307377.12 | c.1378T>C | p.Tyr460His | missense_variant | 13/13 | 1 | |||
GLB1 | ENST00000399402.7 | c.1681T>C | p.Tyr561His | missense_variant | 16/16 | 2 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152216Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000802 AC: 2AN: 249222Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135268
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461634Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727132
GnomAD4 genome ? AF: 0.00000656 AC: 1AN: 152334Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74494
ClinVar
Submissions by phenotype
GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 06, 2022 | 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.Tyr591 amino acid residue in GLB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10737981). 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 missense change has been observed in individual(s) with GM1 gangliosidosis (PMID: 29439846). This variant is present in population databases (rs72555373, gnomAD 0.002%). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 591 of the GLB1 protein (p.Tyr591His). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at