rs397515616
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000404.4(GLB1):āc.319T>Cā(p.Phe107Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 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 ā ). Synonymous variant affecting the same amino acid position (i.e. F107F) has been classified as Likely benign.
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.319T>C | p.Phe107Leu | missense_variant | 3/16 | ENST00000307363.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLB1 | ENST00000307363.10 | c.319T>C | p.Phe107Leu | missense_variant | 3/16 | 1 | NM_000404.4 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249514Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135378
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461894Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727248
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 12, 2016 | - - |
GM1 gangliosidosis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 22, 2024 | Variant summary: GLB1 c.319T>C (p.Phe107Leu) results in a non-conservative amino acid change located in the Glycoside hydrolase 35, catalytic domain (IPR031330) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249514 control chromosomes. c.319T>C has been reported in the literature in compound heterozygous individuals affected with GM1 Gangliosidosis with second variants in trans and cis to the variant (e.g. Hofer_2010, Kannebley_2015). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal beta-galactosidase enzyme activity in both transfected COS-1 cells and in compound heterozygous patient fibroblasts with a second variant with null enzyme activity (e.g. Hofer_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20175788, 26108645). ClinVar contains an entry for this variant (Variation ID: 68478). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 04, 2023 | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 107 of the GLB1 protein (p.Phe107Leu). This variant is present in population databases (rs397515616, gnomAD 0.0009%). This missense change has been observed in individual(s) with GLB1-related conditions (PMID: 20175788). ClinVar contains an entry for this variant (Variation ID: 68478). 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: 20175788). 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. - |
GM1 gangliosidosis type 2 Other:1
not provided, no classification provided | literature only | Laboratory of Molecular Genetics MedGen | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at