rs376710410
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_ModeratePM1PM2PP3_StrongPP5_Very_Strong
The NM_000404.4(GLB1):āc.464T>Gā(p.Leu155Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000014 in 1,573,934 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 (ā ā ). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.
Frequency
Consequence
NM_000404.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLB1 | NM_000404.4 | c.464T>G | p.Leu155Arg | missense_variant | 5/16 | ENST00000307363.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLB1 | ENST00000307363.10 | c.464T>G | p.Leu155Arg | missense_variant | 5/16 | 1 | NM_000404.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000525 AC: 8AN: 152244Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000266 AC: 5AN: 188042Hom.: 0 AF XY: 0.00000993 AC XY: 1AN XY: 100738
GnomAD4 exome AF: 0.00000985 AC: 14AN: 1421690Hom.: 0 Cov.: 31 AF XY: 0.0000128 AC XY: 9AN XY: 703254
GnomAD4 genome ? AF: 0.0000525 AC: 8AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74376
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 31, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 08, 2023 | Published functional studies found L155R is associated with significantly reduced beta-galactosidase activity (Hofer et al., 2009); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17309651, 19472408, 20175788, 31761138, 33240792) - |
Mucopolysaccharidosis, MPS-IV-B Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Mar 02, 2017 | - - |
Mucopolysaccharidosis, MPS-IV-B;C0268271:Infantile GM1 gangliosidosis;C0268272:GM1 gangliosidosis type 2;C0268273:GM1 gangliosidosis type 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 16, 2021 | - - |
GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 20, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 155 of the GLB1 protein (p.Leu155Arg). This variant is present in population databases (rs376710410, gnomAD 0.006%). This missense change has been observed in individual(s) with GM1-gangliosidosis, type I (PMID: 17309651, 19472408, 20175788, 25557439). ClinVar contains an entry for this variant (Variation ID: 265179). 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: 19472408). For these reasons, this variant has been classified as Pathogenic. - |
Infantile GM1 gangliosidosis Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - GM1 | - | Variant interpreted as Pathogenic and reported on 09-13-2014 by Lab or GTR ID 26957. GenomeConnect-GM1 assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at