ClinVar Miner

Submissions for variant NM_000404.4(GLB1):c.622C>T (p.Arg208Cys) (rs72555366)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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.
Invitae RCV000633470 SCV000754699 pathogenic Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis 2020-07-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 208 of the GLB1 protein (p.Arg208Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs72555366, ExAC 0.02%). This variant has been reported in many individuals affected with GM1-gangliosidosis (PMID: 8213816, 17309651, 15714521, 10338095). ClinVar contains an entry for this variant (Variation ID: 939). Experimental studies have shown that this missense change causes GLB1 protein to be misfolded and abrogates enzyme function (PMID: 8213816, 23337983, 15714521). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000179306 SCV001751808 pathogenic not provided 2020-12-03 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: 10338095, 31905715, 32219895, 31761138, 23337983, 17309651, 23046582, 28703315, 8213816, 10571006, 15714521, 20175788, 8652017, 22128166, 29451896)
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

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