Submissions for variant NM_000404.4(GLB1):c.1646C>T (p.Pro549Leu)

gnomAD frequency: 0.00001  dbSNP: rs776327443

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000490151	SCV000576568	pathogenic	not provided	2017-04-27	criteria provided, single submitter	clinical testing	The P549L variant is classified as a severe GLB1 variant associated with type I (infantile) GM1-gangliosidosis phenotype (Santamaria et al. 2007; Caciotti et al. 2007; Higaki et al. 2011; Celtikçi et al. 2012). The P549L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P549L variant is a semi-conservative amino acid substitution that occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, P549 is located in the galactose-binding domain-like structure of the β-galactosidase protein. Variants in this region are expected to be severe as they likely result in changes to the structure of the enzyme's active site and/or substrate binding site (Celtikçi et al. 2012). In summary, we interpret P549L as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000811767	SCV000952052	pathogenic	Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis	2023-11-06	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 549 of the GLB1 protein (p.Pro549Leu). This variant is present in population databases (rs776327443, gnomAD 0.01%). This missense change has been observed in individual(s) with GM1 gangliosidosis (PMID: 17221873, 17309651, 22234367). 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: 426185). 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%. Experimental studies have shown that this missense change affects GLB1 function (PMID: 21520340). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000490151	SCV002024821	pathogenic	not provided	2020-04-08	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV002286741	SCV002577410	pathogenic	Infantile GM1 gangliosidosis	2022-01-12	criteria provided, single submitter	clinical testing	PM2, PM3, PP2, PP3, PP5
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000666099	SCV003934496	pathogenic	Mucopolysaccharidosis, MPS-IV-B	2023-05-09	criteria provided, single submitter	clinical testing	Variant summary: GLB1 c.1646C>T (p.Pro549Leu) results in a non-conservative amino acid change located in the Beta-galactosidase jelly roll domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 248816 control chromosomes. c.1646C>T has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IVB (Morquio Syndrome B). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Celtikci_2012). The following publications have been ascertained in the context of this evaluation (PMID: 17221873, 22234367, 17309651). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl	RCV000666099	SCV000790340	likely pathogenic	Mucopolysaccharidosis, MPS-IV-B	2017-03-16	no assertion criteria provided	clinical testing