Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Foundation for Research in Genetics and Endocrinology, |
RCV001650518 | SCV001870422 | likely pathogenic | Infantile GM1 gangliosidosis | criteria provided, single submitter | clinical testing | A homozygous missense variant in exon 10 of the GLB1 gene that results in the amino acid substitution of Proline for Leucine at codon 337 was detected. The observed variant c.1010T>C (p.Leu337Pro) has not been reported in the 1000 genomes and has a MAF of 0.0004% in the gnomAD databases. The in silico prediction of the variant is damaging by LRT, SIFT, PROVEAN and MutationTaster2. The reference codon is conserved across species. Uniprot classifies this variant as pathogenic and has previously been observed in patients affected with GM1 Gangliosidosis Type 1/2. In summary, the variant meets our criteria to be classified as likely pathogenic. | |
| Kasturba Medical College, |
RCV001650518 | SCV002053880 | pathogenic | Infantile GM1 gangliosidosis | criteria provided, single submitter | clinical testing | ||
| Invitae | RCV001882746 | SCV002236598 | pathogenic | Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis | 2023-04-08 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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: 1251981). This missense change has been observed in individual(s) with GM1 gangliosidosis (PMID: 23151865, 25936995). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs752177002, gnomAD 0.003%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 337 of the GLB1 protein (p.Leu337Pro). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003323912 | SCV004028684 | pathogenic | GM1 gangliosidosis | 2023-07-27 | criteria provided, single submitter | clinical testing | Variant summary: GLB1 c.1010T>C (p.Leu337Pro) 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 allele was found at a frequency of 4e-06 in 249536 control chromosomes. c.1010T>C has been reported in the literature in homozygous and compound heterozygous individuals affected with infantile GM1 Gangliosidosis (e.g. Lei_2012, Bidchol_2015). These data indicate that the variant is very 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 -GAL enzyme activity in homozygous patients with GM1 Gangliosidosis (e.g. Bidchol_2015). The following publications have been ascertained in the context of this evaluation (PMID: 25936995, 23151865). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |