Submissions for variant NM_000404.4(GLB1):c.203G>T (p.Arg68Leu)

dbSNP: rs572237881

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002002980	SCV002276755	likely pathogenic	Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis	2021-07-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with leucine at codon 68 of the GLB1 protein (p.Arg68Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with GLB1-related conditions. 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. This variant disrupts the p.Arg68 amino acid residue in GLB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12644936, 25936995). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323967	SCV004028685	uncertain significance	not specified	2023-07-31	criteria provided, single submitter	clinical testing	Variant summary: GLB1 c.203G>T (p.Arg68Leu) 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. The variant was absent in 249456 control chromosomes (gnomAD). To our knowledge, no occurrence of c.203G>T in individuals affected with Mucopolysaccharidosis Type IVB (Morquio Syndrome B) and no experimental evidence demonstrating its impact on protein function have been reported. Other variants affecting the same codon have been classified pathogenic or likely pathogenic in ClinVar (IDs: 944, 1068202, 195074) suggesting this residue may be critical for normal function of the protein. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.