Submissions for variant NM_000404.4(GLB1):c.248A>G (p.Tyr83Cys)

dbSNP: rs1553612220

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000671078	SCV000796020	uncertain significance	GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis	2017-11-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003767991	SCV004579748	pathogenic	Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 83 of the GLB1 protein (p.Tyr83Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Morquio B (PMID: 16941474, 30138938). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 555286). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GLB1 function (PMID: 17664528). This variant disrupts the p.Tyr83 amino acid residue in GLB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7586649). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005240435	SCV005883541	likely pathogenic	Mucopolysaccharidosis, MPS-IV-B	2024-12-13	criteria provided, single submitter	clinical testing	Variant summary: GLB1 c.248A>G (p.Tyr83Cys) results in a non-conservative amino acid change located in the Glycoside hydrolase 35, catalytic domain (IPR031330) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 248614 control chromosomes (gnomAD). c.248A>G has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IVB (Morquio Syndrome B) (Santamaria_2006, Huang_2018). These data indicate that the variant may be associated with disease. Two publications reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Santamaria_2007, Higaki_2011). The following publications have been ascertained in the context of this evaluation (PMID: 21520340, 30138938, 16941474, 17664528). ClinVar contains an entry for this variant (Variation ID: 555286). Based on the evidence outlined above, the variant was classified as likely pathogenic.