ClinVar Miner

Submissions for variant NM_000158.4(GBE1):c.721A>G (p.Met241Val)

gnomAD frequency: 0.00001  dbSNP: rs747155575
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services,Illumina 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.
Illumina Laboratory Services,Illumina 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.
Institute of Human Genetics, University of Goettingen 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.
Broad Institute Rare Disease Group, Broad Institute 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).

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