chr3-33016750-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_000404.4(GLB1):āc.1438A>Gā(p.Met480Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,614,046 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000404.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000801 AC: 2AN: 249584Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135408
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461850Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727230
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74352
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-IV-B;C0268271:Infantile GM1 gangliosidosis;C0268272:GM1 gangliosidosis type 2;C0268273:GM1 gangliosidosis type 3 Pathogenic:1Uncertain:1
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not provided Pathogenic:1
Reported with a second GLB1 variant, phase unknown, in a patient with infantile GM1-gangliosidosis (Higaki et al., 2011); Published functional studies demonstrate M480V reduced beta-galactosidase activity to approximately 10% of wild-type (Takai et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21520340, 29396849, 23337983) -
Mucopolysaccharidosis, MPS-IV-B Pathogenic:1
Variant summary: GLB1 c.1438A>G (p.Met480Val) results in a conservative amino acid change located in the Beta-galactosidase 1-like , first all-beta domain (IPR048912) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249584 control chromosomes. c.1438A>G has been reported in the literature in at least one compound heterozygous individual affected with GM1-Gangliosidosis (e.g. Higaki_2011). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of beta-galatosidase activity in vrito (e.g. Takai_2013). The following publications have been ascertained in the context of this evaluation (PMID: 21520340, 23337983). ClinVar contains an entry for this variant (Variation ID: 553636). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at