ClinVar Miner

Submissions for variant NM_000404.4(GLB1):c.808T>G (p.Tyr270Asp) (rs376663785)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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
Invitae RCV000689244 SCV000816886 pathogenic Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis 2020-08-26 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with aspartic acid at codon 270 of the GLB1 protein (p.Tyr270Asp). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and aspartic acid. This variant is present in population databases (rs376663785, ExAC 0.004%). This variant has been observed in several individuals affected with GLB1-related conditions (PMID: 21520340, 19472408, 11511921, Invitae). ClinVar contains an entry for this variant (Variation ID: 284172). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 2020-08-19 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 (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32036093, 21520340, 19472408, 11511921, 31761138, 18546276, 20409738, 22784478, 18937943)

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