ClinVar Miner

Submissions for variant NM_021957.4(GYS2):c.547C>T (p.Gln183Ter)

gnomAD frequency: 0.00005  dbSNP: rs201157731
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199810 SCV000251594 pathogenic not provided 2014-07-16 criteria provided, single submitter clinical testing p.Gln183Stop (CAG>TAG): c.547 C>T in exon 4 of the GYS2 gene (NM_021957.3). The Q183X nonsense mutation in the GYS2 gene has been reported in association with glycogen storage disease, type 0. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is found in MITONUC-MITOP panel(s).
Eurofins Ntd Llc (ga) RCV000199810 SCV000860991 pathogenic not provided 2018-04-23 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000763306 SCV000893973 pathogenic Glycogen storage disorder due to hepatic glycogen synthase deficiency 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000763306 SCV001379253 pathogenic Glycogen storage disorder due to hepatic glycogen synthase deficiency 2021-08-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln183*) in the GYS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GYS2 are known to be pathogenic (PMID: 9691087). This variant is present in population databases (rs201157731, ExAC 0.02%). This premature translational stop signal has been observed in individual(s) with glycogen storage disease type 0 (PMID: 12072888). ClinVar contains an entry for this variant (Variation ID: 214529). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000763306 SCV001520627 pathogenic Glycogen storage disorder due to hepatic glycogen synthase deficiency 2022-12-19 criteria provided, single submitter clinical testing
Revvity Omics, Revvity Omics RCV000763306 SCV002024937 pathogenic Glycogen storage disorder due to hepatic glycogen synthase deficiency 2020-06-29 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000763306 SCV002766882 pathogenic Glycogen storage disorder due to hepatic glycogen synthase deficiency 2022-03-31 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with liver glycogen storage disease 0 (MIM#240600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are reported to have variable clinical phenotypes (PMIDs: 32395408, 28245189, 18341095). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (13 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in patients with glycogen storage disease type 0 (ClinVar, PMIDs: 12072888, 32377253). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity and has previously been reported in patients with glycogen storage disease 0 (ClinVar, PMID: 32395408). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant in a recessive disease. (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Broad Institute Rare Disease Group, Broad Institute RCV000763306 SCV003761320 pathogenic Glycogen storage disorder due to hepatic glycogen synthase deficiency 2023-01-25 criteria provided, single submitter curation The heterozygous p.Gln183Ter variant in GYS2 was identified by our study in one individual with hypotonia. The p.Gln183Ter variant in GYS2 has been previously reported in two unrelated individuals with liver glycogen storage disorder 0 but has been identified in 0.01% (9/68028) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs201157731). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. These two affected individuals (PMID: 12072888, PMID: 32377253) were compound heterozygous who carried pathogenic or likely pathogenic variants in trans (PMID: 12072888, PMID: 32377253, ClinVar Variation ID: 937499), which increases the likelihood that the p.Gln183Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 214529) and has been interpreted as pathogenic by multiple submitters. This nonsense variant leads to a premature termination codon at position 183, which is predicted to lead to a truncated or absent protein. Loss of function of the GYS2 gene is strongly associated to autosomal recessive liver glycogen storage disorder 0. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive liver glycogen storage disorder 0. ACMG/AMP Criteria applied: PVS1_Strong, PM3_Strong (Richards 2015).
3billion RCV000763306 SCV003841517 pathogenic Glycogen storage disorder due to hepatic glycogen synthase deficiency 2023-02-23 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). This homozygous variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000214529 / PMID: 12072888). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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