Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000017431 | SCV000914578 | uncertain significance | Glycogen storage disorder due to hepatic glycogen synthase deficiency | 2017-09-07 | criteria provided, single submitter | clinical testing | The GYS2 c.1472T>G (p.Met491Arg) missense variant has been reported in a single study in one individual with glycogen storage disease type 0, liver, in a compound heterozygous state with a second missense variant (Orho et al. 1998). Familial testing identified the patient's father as a heterozygous carrier of the p.Met491Arg variant, which was absent in the patient's unaffected sister. The p.Met491Arg variant was absent from 200 controls and is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium but this is based on one allele only and is presumed to be rare. Assessment of glycogen synthase activity of the variant in COS7 cells identified activity levels less than or equal to 3.5% of wild type activity (Orho et al. 1998). Based on the limited evidence, the p.Met491Arg variant is classified as a variant of unknown significance but suspicious for pathogenicity for glycogen storage disease type 0, liver. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Labcorp Genetics |
RCV000017431 | SCV002137080 | likely pathogenic | Glycogen storage disorder due to hepatic glycogen synthase deficiency | 2022-06-28 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with glycogen storage disease (PMID: 9691087). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121918422, gnomAD 0.0009%). This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 491 of the GYS2 protein (p.Met491Arg). ClinVar contains an entry for this variant (Variation ID: 16053). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects GYS2 function (PMID: 9691087). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. |
| OMIM | RCV000017431 | SCV000037703 | pathogenic | Glycogen storage disorder due to hepatic glycogen synthase deficiency | 1998-08-01 | no assertion criteria provided | literature only |