ClinVar Miner

Submissions for variant NM_000404.4(GLB1):c.1313G>A (p.Gly438Glu)

dbSNP: rs72555367
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000850556 SCV000992770 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 RCV001091796 SCV001248012 pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001091796 SCV001446656 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001382999 SCV001581998 pathogenic Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis 2024-09-05 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 438 of the GLB1 protein (p.Gly438Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GM1 gangliosidosis and mucopolysaccharidosis IVB (PMID: 10841810, 19472408, 21497194, 23831247, 26646981). ClinVar contains an entry for this variant (Variation ID: 940). 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: 19472408). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001091796 SCV001811050 pathogenic not provided 2022-10-03 criteria provided, single submitter clinical testing Functional studies found this variant is associated with significantly reduced beta-galactosidase activity (Hofer et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33737400, 10841810, 19472408, 20629163, 15986423, 23831247, 22033734, 31216405)
Génétique des Maladies du Développement, Hospices Civils de Lyon RCV001843450 SCV002102989 pathogenic Spondyloepiphyseal dysplasia 2022-03-09 criteria provided, single submitter clinical testing recurrent pathogenic variant
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV005237344 SCV005885292 pathogenic GM1 gangliosidosis 2025-02-24 criteria provided, single submitter clinical testing Variant summary: GLB1 c.1313G>A (p.Gly438Glu) results in a non-conservative amino acid change located in the Beta-galactosidase, first all-beta domain (IPR048912) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249588 control chromosomes. c.1313G>A has been reported in the literature in multiple individuals affected with GM1 Gangliosidosis and related conditions (Hofer_2009, Fantur_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Hofer_2009).The following publications have been ascertained in the context of this evaluation (PMID: 19472408, 22033734). ClinVar contains an entry for this variant (Variation ID: 940). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000000989 SCV000021139 pathogenic Mucopolysaccharidosis, MPS-IV-B 2021-05-04 no assertion criteria provided literature only

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