rs72555393
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong
The NM_000404.4(GLB1):c.245C>T(p.Thr82Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,612,964 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.
Frequency
Consequence
NM_000404.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000521 AC: 13AN: 249296Hom.: 0 AF XY: 0.0000665 AC XY: 9AN XY: 135248
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1460814Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 726718
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74316
ClinVar
Submissions by phenotype
GM1 gangliosidosis type 3 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 1994 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense c.245C>T p.Thr82Met variant in the GLB1 gene has been observed in individuals with GM1-gangliosidosis Hofer, D et al., 2010. It has also been observed to segregate with disease in related individuals. Functional studies demonstrate decreased enzyme activity Chakraborty et al., 1994. This variant is reported with the allele frequency 0.005% in the gnomAD Exomes and novel in 1000 Genomes. It is submitted to ClinVar as Likely Pathogenic/Uncertain significance/Pathogenic multiple submissions. The amino acid Threonine at position 82 is changed to a Methionine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Thr82Met in GLB1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. 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 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 20, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 30, 2017 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 26, 2016 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 25, 2021 | Published functional studies demonstrate decreased enzyme activity (Chakraborty et al., 1994); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19472408, 11511921, 31367523, 8198123, 24024947, 25326637, 20175788, 31761138, 31937438, 31628766, 21520340, 6791574, 33240792) - |
GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 11, 2024 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 82 of the GLB1 protein (p.Thr82Met). This variant is present in population databases (rs72555393, gnomAD 0.009%). This missense change has been observed in individual(s) with GM1-gangliosidosis (PMID: 8198123, 11511921, 20175788, 21520340, 25326637). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 935). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects GLB1 function (PMID: 8198123). For these reasons, this variant has been classified as Pathogenic. - |
Infantile GM1 gangliosidosis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The stop gain c.1324C>T p.Arg442Ter variant in GLB1 gene has been reported to the ClinVar database as Pathogenic. To our knowledge, this variant has not been reported in literature in individuals affected with GLB1-associated disorder. The c.1324C>T variant is novel not in any individuals in both gnomAD Exomes and 1000 Genomes databases. The nucleotide change c.1324C>T in GLB1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in GLB1 gene have been previously reported to be disease causing. Additional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at