ClinVar Miner

Submissions for variant NM_021957.4(GYS2):c.1436C>A (p.Pro479Gln) (rs121918420)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000017429 SCV000377428 uncertain significance Glycogen storage disease due to hepatic glycogen synthase deficiency 2017-04-27 criteria provided, single submitter clinical testing The GYS1 c.1436C>A (p.Pro479Gln) missense variant has been reported in one study in which it was found in a compound heterozygous state with a canonical donor splice variant in three siblings with glycogen storage disease type 0, liver disease (Orho et al. 1998). Functional studies showed that COS-7 cells transfected with a GYS2 construct containing the p.Pro479Gln variant had no glycogen synthase activity (Orho et al. 1998). The p.Pro479Gln variant was absent from 200 controls and is reported at a frequency of 0.00020 in the European (non-Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Pro479Gln variant is classified as unknown significance, but suspicious for pathogenicity for glycogen storage disease type 0. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000017429 SCV000763893 uncertain significance Glycogen storage disease due to hepatic glycogen synthase deficiency 2017-08-16 criteria provided, single submitter clinical testing This sequence change replaces proline with glutamine at codon 479 of the GYS2 protein (p.Pro479Gln). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and glutamine. This variant is present in population databases (rs121918420, ExAC 0.02%). This variant has been reported to segregate with glycogen storage disease type 0 in a single family and it has been observed on the opposite chromosome (in trans) from another pathogenic variant in individuals affected with this condition (PMID: 9691087). This latter finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 16051). Experimental studies have shown that this missense change results in abrogation of GYS2 enzyme activity (PMID: 9691087). 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.
GeneDx RCV001582484 SCV001811915 pathogenic not provided 2018-10-11 criteria provided, single submitter clinical testing Published expression studies demonstrate that variant is associated with no detectable glycogen synthase activity (Orho et al., 1998); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 9691087)
OMIM RCV000017429 SCV000037701 pathogenic Glycogen storage disease due to hepatic glycogen synthase deficiency 1998-08-01 no assertion criteria provided literature only

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