ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000623067 SCV000741501 pathogenic Inborn genetic diseases 2016-04-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Counsyl RCV000666452 SCV000790747 likely pathogenic GM1 gangliosidosis type 2; Gangliosidosis GM1 type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis 2017-04-06 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000394616 SCV000336686 pathogenic not provided 2015-10-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000689244 SCV000816886 pathogenic Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis 2018-06-21 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 to be homozygous or in combination with another GLB1 variants in several individuals affected with GM1 gangliosidosis (PMID: 19472408, 23151865). Experimental studies have shown that this missense change abrogates GLB1 enzymatic activity (PMID: 23151865). The observation of one or more missense substitutions at this codon (p.Tyr270Phe and p.Tyr270Asp) in affected individuals suggests that this may be a clinically significant residue (PMID: 23151865, 19472408, 23151865). For these reasons, this variant has been classified as Pathogenic.

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