Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000674446 | SCV000799784 | likely pathogenic | GM1 gangliosidosis type 2; GM1 gangliosidosis type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis | 2018-05-11 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001855609 | SCV002236354 | pathogenic | Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis | 2023-10-09 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 346 of the GLB1 protein (p.Lys346Asn). This variant is present in population databases (rs749980306, gnomAD 0.0009%). A different variant (c.1038G>C) giving rise to the same protein effect has been determined to be pathogenic (PMID: 16941474, 23337983, 24777551). This suggests that this variant is also likely to be causative of disease. ClinVar contains an entry for this variant (Variation ID: 558213). 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. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002271564 | SCV002555708 | likely pathogenic | GM1 gangliosidosis | 2022-06-07 | criteria provided, single submitter | clinical testing | Variant summary: GLB1 c.1038G>T (p.Lys346Asn) results in a non-conservative amino acid change located in the Glycoside hydrolase 35, catalytic 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 4e-06 in 249536 control chromosomes. c.1038G>T has been reported in the literature in one individual affected with GM1 Gangliosidosis (Hofer_2009). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity (Takai_2013). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |