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

Total submissions: 18

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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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	2020-09-24	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	2020-05-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana	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 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
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000078708	SCV001744239	pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV000000995	SCV001821206	pathogenic	Infantile GM1 gangliosidosis	2021-04-19	no assertion criteria provided	literature only	High prevalence in Roma and Brazilian populations; associated with GM1 infantile and juvenile forms
Human Genetics - Radboudumc,Radboudumc	RCV000078708	SCV001952022	pathogenic	not provided		no assertion criteria provided	clinical testing