rs201807974
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PM5BP4
The NM_000404.4(GLB1):c.1783C>T(p.Arg595Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R595Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000404.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLB1 | NM_000404.4 | c.1783C>T | p.Arg595Trp | missense_variant | 16/16 | ENST00000307363.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLB1 | ENST00000307363.10 | c.1783C>T | p.Arg595Trp | missense_variant | 16/16 | 1 | NM_000404.4 | P2 | |
GLB1 | ENST00000307377.12 | c.1390C>T | p.Arg464Trp | missense_variant | 13/13 | 1 | |||
GLB1 | ENST00000399402.7 | c.1693C>T | p.Arg565Trp | missense_variant | 16/16 | 2 | A2 |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152190Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000120 AC: 30AN: 249362Hom.: 0 AF XY: 0.0000739 AC XY: 10AN XY: 135308
GnomAD4 exome AF: 0.0000602 AC: 88AN: 1461768Hom.: 0 Cov.: 31 AF XY: 0.0000523 AC XY: 38AN XY: 727186
GnomAD4 genome AF: 0.000125 AC: 19AN: 152308Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74478
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-IV-B;C0268271:Infantile GM1 gangliosidosis;C0268272:GM1 gangliosidosis type 2;C0268273:GM1 gangliosidosis type 3 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 22, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 27, 2016 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 16, 2021 | Variant summary: GLB1 c.1783C>T (p.Arg595Trp) results in a non-conservative amino acid change located in the Beta-galactosidase jelly roll domain (IPR025300) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 249362 control chromosomes, predominantly at a frequency of 0.00075 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in GLB1 causing Mucopolysaccharidosis Type IVB (Morquio Syndrome B) (0.00012 vs 0.00091), allowing no conclusion about variant significance. c.1783C>T has been reported in the literature as a compound heterozygous genotype with another pathogenic allele in trans in the clinically unaffected father of an individual with GM1 gangliosidosis (Gort_2007). The disease in the affected individual was attributed to a biallelic genotype comprising the pathogenic allele from this unaffected father and another pathogenic allele from the obligate carrier mother, but not to this variant. Further biochemical workup of the healthy father revealed a pseudodeficient beta galactosidase enzyme activity in both his leukocytes and plasma. These report(s) do not provide unequivocal conclusions about association of the variant with Mucopolysaccharidosis Type IVB (Morquio Syndrome B). At least one publication reports experimental evidence evaluating an impact on protein function (Gort_2007). The most pronounced variant effect results in 33-59% of normal enzyme activity when this variant was traniently expressed in-vitro. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as a pseudodeficiency allele of uncertain significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 10, 2022 | The c.1783C>T (p.R595W) alteration is located in exon 16 (coding exon 16) of the GLB1 gene. This alteration results from a C to T substitution at nucleotide position 1783, causing the arginine (R) at amino acid position 595 to be replaced by a tryptophan (W). The alteration is predicted deleterious by in silico models:_x000D_ The p.R595W alteration is predicted to be possibly damaging by Polyphen and deleterious by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
See cases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Oct 21, 2020 | ACMG classification criteria: PM2, PM3 - |
GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 24, 2022 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 595 of the GLB1 protein (p.Arg595Trp). This variant is present in population databases (rs201807974, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with GLB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 550288). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GLB1 protein function. Experimental studies have shown that this missense change affects GLB1 function (PMID: 17661814). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
GM1 gangliosidosis type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at