ClinVar Miner

Submissions for variant NM_000404.4(GLB1):c.1769G>A (p.Arg590His)

gnomAD frequency: 0.00003  dbSNP: rs398123351
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000174999 SCV000226418 pathogenic not provided 2013-11-06 criteria provided, single submitter clinical testing
Invitae RCV000794211 SCV000933605 pathogenic Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis 2023-11-19 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 590 of the GLB1 protein (p.Arg590His). This variant is present in population databases (rs398123351, gnomAD 0.003%). This missense change has been observed in individuals with GM1-gangliosidosis (PMID: 8213816, 26646981). ClinVar contains an entry for this variant (Variation ID: 92901). 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: 8213816, 23337983). This variant disrupts the p.Arg590 amino acid residue in GLB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16941474, 17309651, 23430803). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India RCV001804833 SCV002053883 pathogenic Infantile GM1 gangliosidosis criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV001810420 SCV002060386 likely pathogenic GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Infantile GM1 gangliosidosis 2021-11-03 criteria provided, single submitter clinical testing NM_000404.2(GLB1):c.1769G>A(R590H) is a missense variant classified as likely pathogenic in the context of GLB1-related disorders. R590H has been observed in cases with relevant disease (PMID: 8213816, 27619815, Shekar_2019_(no PMID; poster), 26646981, 33737400). Functional assessments of this variant are available in the literature (PMID: 8213816, 21520340, 23337983). R590H has been observed in population frequency databases (gnomAD: SAS 0.003%). In summary, NM_000404.2(GLB1):c.1769G>A(R590H) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

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