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

gnomAD frequency: 0.00001  dbSNP: rs376663785

Total submissions: 9

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
Invitae	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	RCV001801701	SCV002047669	not provided	GLB1-Related Disorders		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.