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

gnomAD frequency: 0.00004  dbSNP: rs72555392

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078708	SCV000227115	pathogenic	not provided	2013-02-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000078708	SCV000490538	pathogenic	not provided	2021-11-11	criteria provided, single submitter	clinical testing	Functional studies in COS-1 cells found that this variant is associated with no residual enzyme activity (Caciotti et al., 2005; Santamaria et al., 2007); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17664528, 10338095, 15714521, 28939701, 10737981, 16466959, 16941474, 31761138, 31216405, 32036093, 33726816)
Illumina Laboratory Services, 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	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 59 of the GLB1 protein (p.Arg59His). This variant is present in population databases (rs72555392, gnomAD 0.009%). This missense change has been observed in individuals with GM1 gangliosidosis (PMID: 10338095, 16941474, 17309651, 17664528). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 945). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GLB1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GLB1 function (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 Center for Human Genetics Tuebingen	RCV000078708	SCV001248014	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	GLB1: PM3:Very Strong, PM1, PM2, PM5, PP4:Moderate, PS3:Supporting
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.
DASA	RCV001813729	SCV002061268	pathogenic	GLB1-Related Disorders	2022-01-05	criteria provided, single submitter	clinical testing	The c.176G>A;p.(Arg59His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 945; PMID: 10338095; 21637542; 17309651; 16941474; 10737981) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 17664528; 15714521; 31776384) - PS3_moderate. The variant is present at low allele frequencies population databases (rs72555392– gnomAD 0.0003607%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg59His) was detected in trans with a pathogenic variant (PMID: 10338095; 17309651; 16941474; 10737981) - PM3_very strong Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000000995	SCV002512229	pathogenic	Infantile GM1 gangliosidosis	2021-07-27	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM3 very strong, PP3 supporting, PP4 supporting
MGZ Medical Genetics Center	RCV000000995	SCV002579350	pathogenic	Infantile GM1 gangliosidosis	2021-07-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000850557	SCV002788809	pathogenic	GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis	2021-08-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000078708	SCV003826416	pathogenic	not provided	2022-03-29	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
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000078708	SCV001744239	pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV000000995	SCV001821206	not provided	Infantile GM1 gangliosidosis		no assertion provided	literature only	High prevalence in Roma and Brazilian populations; associated with GM1 infantile and juvenile forms
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000078708	SCV001952022	pathogenic	not provided		no assertion criteria provided	clinical testing