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

Total submissions: 14

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