ClinVar Miner

Submissions for variant NM_000404.4(GLB1):c.808T>G (p.Tyr270Asp)

gnomAD frequency: 0.00001  dbSNP: rs376663785
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000394616 SCV000336686 pathogenic not provided 2015-10-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000623067 SCV000741501 pathogenic Inborn genetic diseases 2016-04-26 criteria provided, single submitter clinical testing
Counsyl RCV000666452 SCV000790747 likely pathogenic GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis 2017-04-06 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000689244 SCV000816886 pathogenic Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis 2023-12-13 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 270 of the GLB1 protein (p.Tyr270Asp). This variant is present in population databases (rs376663785, gnomAD 0.005%). This missense change has been observed in individual(s) with GLB1-related conditions (PMID: 11511921, 19472408, 21520340; Invitae). ClinVar contains an entry for this variant (Variation ID: 284172). 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%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780303 SCV000917465 pathogenic Mucopolysaccharidosis, MPS-IV-B 2018-02-08 criteria provided, single submitter clinical testing Variant summary: GLB1 c.808T>G (p.Tyr270Asp) results in a non-conservative amino acid change located in the catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. The variant allele was found at a frequency of 2.2e-05 in 6/277174 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GLB1 causing Mucopolysaccharidosis Type IVB (Morquio Syndrome B) (2.2e-05 vs 0.00091), allowing no conclusion about variant significance. The c.808T>G has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVB (Morquio Syndrome B) and GM1 gangliosidosis. These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000394616 SCV001447100 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
GeneDx RCV000394616 SCV001826789 pathogenic not provided 2022-09-29 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: undetectable enzyme activity (Hofer et al., 2009; Higaki et al., 2011); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 18937943, 20409738, 21520340, 18546276, 33737400, 22784478, 19472408, 31761138, 11511921, 32036093, 34691145)
MGZ Medical Genetics Center RCV000780303 SCV002579115 likely pathogenic Mucopolysaccharidosis, MPS-IV-B 2022-04-14 criteria provided, single submitter clinical testing
GenomeConnect - GM1 RCV004545765 SCV002047669 not provided GLB1-related disorder no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 10-29-2018 by lab or GTR ID Centogene. 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. Phenotypic details are available under supporting information.

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