Submissions for variant NM_000404.4(GLB1):c.622C>T (p.Arg208Cys)

gnomAD frequency: 0.00012  dbSNP: rs72555366

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000179306	SCV000231535	pathogenic	not provided	2013-12-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586182	SCV000696688	pathogenic	GM1 gangliosidosis	2017-05-02	criteria provided, single submitter	clinical testing	Variant summary: The GLB1 c.622C>T (p.Arg208Cys) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome. This variant was found in 7/120010 control chromosomes at a frequency of 0.0000583, which does not exceed the estimated maximal expected allele frequency of a pathogenic GLB1 variant (0.0020412). Multiple publications have cited the variant in affected individuals as homozygotes and compound heterozygotes, and observed little to no enzymatic activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000633470	SCV000754699	pathogenic	Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis	2024-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 208 of the GLB1 protein (p.Arg208Cys). This variant is present in population databases (rs72555366, gnomAD 0.02%). This missense change has been observed in individuals with GM1-gangliosidosis (PMID: 8213816, 10338095, 15714521, 17309651). ClinVar contains an entry for this variant (Variation ID: 939). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 8213816, 15714521, 23337983). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000179306	SCV001751808	pathogenic	not provided	2022-02-16	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that the R208C variant abolishes the catalytic activity of the -galactosidase enzyme (Boustany et al., 1993); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28703315, 22128166, 29451896, 8213816, 8652017, 20175788, 15714521, 10571006, 23046582, 17309651, 23337983, 31761138, 32219895, 31905715, 10338095)
Revvity Omics, Revvity	RCV000179306	SCV002024822	pathogenic	not provided	2020-12-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002512629	SCV003696359	pathogenic	Inborn genetic diseases	2022-01-21	criteria provided, single submitter	clinical testing	The c.622C>T (p.R208C) alteration is located in exon 6 (coding exon 6) of the GLB1 gene. This alteration results from a C to T substitution at nucleotide position 622, causing the arginine (R) at amino acid position 208 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of <0.01% (11/249146) total alleles studied. This variant has been reported in the homozygous state and confirmed or presumed in trans with a second GLB1 variant in patients with GM1-gangliosidosis (Boustany, 1993; Silva, 1999; Caciotti, 2005; Santamaria, 2007; Arash-Kaps, 2019). This amino acid position is not well conserved in available vertebrate species. In vitro studies demonstrated that this variant abolished catalytic activity of the beta-galactosidase protein in transfected COS-1 cells (Boustany, 1993). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005024980	SCV005658108	pathogenic	GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis	2024-05-16	criteria provided, single submitter	clinical testing
OMIM	RCV000000988	SCV000021138	pathogenic	Infantile GM1 gangliosidosis	1996-01-01	no assertion criteria provided	literature only
Counsyl	RCV000000988	SCV001132405	pathogenic	Infantile GM1 gangliosidosis	2017-02-03	no assertion criteria provided	clinical testing
Counsyl	RCV000984269	SCV001132406	pathogenic	GM1 gangliosidosis type 2	2017-02-03	no assertion criteria provided	clinical testing
Counsyl	RCV000984270	SCV001132407	pathogenic	GM1 gangliosidosis type 3	2017-02-03	no assertion criteria provided	clinical testing
Counsyl	RCV000984271	SCV001132408	pathogenic	Mucopolysaccharidosis, MPS-IV-B	2017-02-03	no assertion criteria provided	clinical testing
GenomeConnect - GM1	RCV000586182	SCV002818102	not provided	GM1 gangliosidosis		no assertion provided	phenotyping only	Variant classified as Pathogenic and reported on 06-01-2020 by Lab or GTR ID 26957. GenomeConnect-GM1 assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant.