ClinVar Miner

Submissions for variant NM_000404.4(GLB1):c.1646C>T (p.Pro549Leu) (rs776327443)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000666099 SCV000790340 likely pathogenic GM1 gangliosidosis type 2; Gangliosidosis GM1 type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis 2017-03-16 criteria provided, single submitter clinical testing
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.
Invitae RCV000811767 SCV000952052 likely pathogenic Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis 2018-08-27 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 549 of the GLB1 protein (p.Pro549Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs776327443, ExAC 0.01%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic pathogenic variant in an individual affected with GM1 gangliosidosis and to be in combination with GLB1 variants in several individuals affected with the same disease (PMID: 17221873, 17309651, 22234367). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 426185). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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