Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Prevention |
RCV004530401 | SCV004115143 | likely pathogenic | GBE1-related disorder | 2023-03-07 | criteria provided, single submitter | clinical testing | The GBE1 c.721A>G variant is predicted to result in the amino acid substitution p.Met241Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-81695604-T-C). This variant was reported in ClinVar in an individual with glycogen storage disease IV, detected in compound heterozygosity with a second pathogenic variant in GBE1 (https://www.ncbi.nlm.nih.gov/clinvar/variation/346793). This variant is classified as likely pathogenic. |
| Labcorp Genetics |
RCV002523458 | SCV003278997 | uncertain significance | Glycogen storage disease, type IV; Glycogen storage disease IV, classic hepatic | 2024-07-16 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 241 of the GBE1 protein (p.Met241Val). This variant is present in population databases (rs747155575, gnomAD 0.005%). This missense change has been observed in individual(s) with GBE1-related conditions (PMID: 33879512). ClinVar contains an entry for this variant (Variation ID: 346793). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GBE1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Broad Center for Mendelian Genomics, |
RCV000329970 | SCV002097117 | uncertain significance | Glycogen storage disease, type IV | 2022-01-27 | criteria provided, single submitter | curation | The p.Met241Val variant in GBE1 has been reported in 1 individual, in the compound heterozygous state, with glycogen storage disease type IV (GSD IV) (ClinVar Variation ID: 346793) and has been identified in 0.005% (6/110798) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs781198373). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 346793) and has been interpreted as likely pathogenic by Clinical Genetics laboratory (University of Goettingen). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Met241Val variant is uncertain. ACMG/AMP Criteria applied: PM3, PP3, PM2_supporting (Richards 2015). |
| Institute of Human Genetics, |
RCV000329970 | SCV001478066 | likely pathogenic | Glycogen storage disease, type IV | 2021-01-23 | criteria provided, single submitter | clinical testing | The GBE1 variant c.721A>G (p.(Met241Val)) is found at a population frequency of 0.0029% in the gnomAD database, it affects a highly conserved nucleotide and a highly conserved amino acid and there is a small physicochemical difference between Met and Val. It is located within a protein domain and has a pathogenic computational verdict based on in silico prediction programs (M-CAP, SIFT, MutationTaster, PolyPhen-2). In our clinic this variant was found in compound-heterozygosity with the splice site variant c.691+2T>C (dbSNP: rs192044702), which is known to cause Glycogen storage disease type IV (OMIM: 232500) when in homozygous or compound heterozygous state. Thus, we consider the c.721A>G variant to be likely pathogenic. ACMG criteria used for classification: PM1, PM2, PM3, PP2, PP3. |
| Illumina Laboratory Services, |
RCV000329970 | SCV000446307 | uncertain significance | Glycogen storage disease, type IV | 2018-01-13 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. |
| Illumina Laboratory Services, |
RCV000272591 | SCV000446306 | uncertain significance | Adult polyglucosan body disease | 2018-01-13 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. |