ClinVar Miner

Submissions for variant NM_000404.4(GLB1):c.176G>A (p.Arg59His) (rs72555392)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078708 SCV000227115 pathogenic not provided 2013-02-18 criteria provided, single submitter clinical testing
GeneDx 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,Illumina 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 2018-09-10 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
CeGaT Praxis fuer Humangenetik Tuebingen RCV000078708 SCV001248014 pathogenic not provided 2020-03-01 criteria provided, single submitter clinical testing
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 MedGen 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

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