Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Institute Of Human Genetics Munich, |
RCV000995552 | SCV001149787 | pathogenic | GM1 gangliosidosis type 2 | 2019-06-11 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV001331204 | SCV001523192 | likely pathogenic | Infantile GM1 gangliosidosis | 2020-05-05 | criteria provided, single submitter | clinical testing | This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. |
| Invitae | RCV001378118 | SCV001575618 | pathogenic | Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis | 2023-08-14 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GLB1 function (PMID: 15714521). 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. ClinVar contains an entry for this variant (Variation ID: 807421). This missense change has been observed in individual(s) with GM1-gangliosidosis (PMID: 15714521, 19472408). This variant is present in population databases (rs746766232, gnomAD 0.003%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 239 of the GLB1 protein (p.Thr239Met). |
| Gene |
RCV002279689 | SCV002567394 | pathogenic | not provided | 2022-08-17 | criteria provided, single submitter | clinical testing | Functional analysis found that T239M is associated with significantly reduced enzyme activity (Caciotti et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29396849, 15714521, 19472408, 33737400) |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003226413 | SCV003922652 | likely pathogenic | Mucopolysaccharidosis, MPS-IV-B | 2023-03-28 | criteria provided, single submitter | clinical testing | Variant summary: GLB1 c.716C>T (p.Thr239Met) results in a non-conservative amino acid change located in the Glycoside hydrolase 35, catalytic domain (IPR031330) of the encoded protein sequence. Four of four 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 249238 control chromosomes (gnomAD). c.716C>T has been reported in the literature in individuals affected with GM1-gangliosidosis (example: Caciotti_2005 and Hofer_2009). These data indicate that the variant may 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 (example: Caciotti_2005). Four diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |