Submissions for variant NM_000404.4(GLB1):c.203G>A (p.Arg68Gln)

gnomAD frequency: 0.00002  dbSNP: rs572237881

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000175606	SCV000227123	pathogenic	not provided	2015-02-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001201192	SCV001372261	likely pathogenic	GM1 gangliosidosis	2020-06-22	criteria provided, single submitter	clinical testing	Variant summary: GLB1 c.203G>A (p.Arg68Gln) results in a conservative amino acid change located in the Glycoside hydrolase 35, catalytic domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249456 control chromosomes. c.203G>A has been reported in the literature in at least one individual affected with GM1 Gangliosidosis (Hofer_2009). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Hofer_2009). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic, and one laboratory classified the variant as uncertain significance. In addition, p.R68W has been reported to associate with Gangliosidosis GM1 (HGMD database), indicating R68 is critical for GLB1 function. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852152	SCV002235170	pathogenic	Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 68 of the GLB1 protein (p.Arg68Gln). This variant is present in population databases (rs572237881, gnomAD 0.01%). This missense change has been observed in individual(s) with GM1 gangliosidosis (PMID: 19472408, 29439846). ClinVar contains an entry for this variant (Variation ID: 195074). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GLB1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GLB1 function (PMID: 19472408). 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; internal data). 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.
Fulgent Genetics, Fulgent Genetics	RCV000673880	SCV005662463	likely pathogenic	GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis	2024-01-07	criteria provided, single submitter	clinical testing
Counsyl	RCV000673880	SCV000799133	uncertain significance	GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis	2018-04-10	flagged submission	clinical testing