Total submissions: 15
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
EGL Genetic Diagnostics, |
RCV000078708 | SCV000227115 | pathogenic | not provided | 2013-02-18 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000078708 | SCV000490538 | pathogenic | not provided | 2018-10-02 | criteria provided, single submitter | clinical testing | The R59H variant in the GLB1 gene is a common variant in patients with type I (infantile) GM1-gangliosidosis from Brazil having been identified on 20% of alleles from affected patients (Silva et al., 1999). Functional studies in COS-1 cells found that R59H is associated with no residual enzyme activity (Caciotti et al., 2005). The R59H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R59H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in the same (R59C) and nearby residues (S54N, S54I) have been reported in the Human Gene Mutation Database in association with GM1-gangliosidosis (Stenson et al., 2014). We interpret R59H as a pathogenic variant. |
Illumina Clinical Services Laboratory, |
RCV000778693 | SCV000915044 | pathogenic | GM1 gangliosidosis | 2018-03-08 | criteria provided, single submitter | clinical testing | Across a selection of the available literature, the GLB1 c.176G>A (p.Arg59His) missense variant has been reported in at least three studies and is found in at least 15 individuals with GM1-gangliosidosis, including in ten in a homozygous state and in five in a compound heterozygous state (Silva et al. 1999; Morrone et al. 2000; Santamaria et al. 2007). All of the reported probands presented with infantile GM1-gangliosidosis. The p.Arg59His variant was absent from 200 control chromosomes and is reported at a frequency of 0.000089 in the Latino population of the Genome Aggregation Database. Functional analysis in proband fibroblasts and COS-7 cells found that the p.Arg59His variant exhibited a nearly complete loss of enzymatic activity compared to wild type (Santamaria et al. 2007). Based on the evidence, the p.Arg59His variant is classified as pathogenic for GM1-gangliosidosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
Integrated Genetics/Laboratory Corporation of America | RCV000175600 | SCV000919467 | pathogenic | Mucopolysaccharidosis, MPS-IV-B | 2018-11-29 | criteria provided, single submitter | clinical testing | Variant summary: GLB1 c.176G>A (p.Arg59His) results in a non-conservative amino acid change located in the Glycoside hydrolase 35, catalytic domain 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 4.1e-05 in 120758 control chromosomes. c.176G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVB (Morquio Syndrome B) (Santamaria_2007, Silva_1999), in which two homozygote patients were found to have <10% enzyme activity (Santamaria_2007). These data indicate that the variant is very likely to be associated with disease. A ClinVar submssion from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Invitae | RCV000811276 | SCV000951534 | pathogenic | Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis | 2019-11-13 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with histidine at codon 59 of the GLB1 protein (p.Arg59His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs72555392, ExAC 0.009%). This variant has been observed to be homozygous or in combination with another GLB1 variant in individuals affected with GM1 gangliosidosis (PMID: 10338095, 16941474, 17664528, 17309651). ClinVar contains an entry for this variant (Variation ID: 945). Experimental studies have shown that this missense change abolishes GLB1 enzyme activity (PMID: 17664528). For these reasons, this variant has been classified as Pathogenic. |
Baylor Genetics | RCV000850557 | SCV000992771 | pathogenic | GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis | 2012-07-03 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000078708 | SCV001248014 | pathogenic | not provided | 2020-05-01 | criteria provided, single submitter | clinical testing | |
Centre for Mendelian Genomics, |
RCV000984179 | SCV001370082 | likely pathogenic | GM1 gangliosidosis type 3 | 2019-01-09 | criteria provided, single submitter | clinical testing | This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3,PP2. |
OMIM | RCV000000994 | SCV000021144 | pathogenic | GM1-gangliosidosis, type I, with cardiac involvement | 2007-03-01 | no assertion criteria provided | literature only | |
OMIM | RCV000000995 | SCV000021145 | pathogenic | Infantile GM1 gangliosidosis | 2007-03-01 | no assertion criteria provided | literature only | |
Laboratory of Molecular Genetics Med |
RCV000059350 | SCV000105913 | not provided | GM1 gangliosidosis type 2 | no assertion provided | not provided | ||
Counsyl | RCV000000995 | SCV001132205 | pathogenic | Infantile GM1 gangliosidosis | 2017-12-18 | no assertion criteria provided | clinical testing | |
Counsyl | RCV000059350 | SCV001132206 | pathogenic | GM1 gangliosidosis type 2 | 2017-12-18 | no assertion criteria provided | clinical testing | |
Counsyl | RCV000984179 | SCV001132207 | pathogenic | GM1 gangliosidosis type 3 | 2017-12-18 | no assertion criteria provided | clinical testing | |
Counsyl | RCV000175600 | SCV001132208 | pathogenic | Mucopolysaccharidosis, MPS-IV-B | 2017-12-18 | no assertion criteria provided | clinical testing |