ClinVar Miner

Submissions for variant NM_021957.4(GYS2):c.736C>T (p.Arg246Ter) (rs121918419)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000605157 SCV000711744 likely pathogenic Glycogen storage disease 2015-12-17 criteria provided, single submitter clinical testing The p.Arg246X variant in GYS2 has been reported in 2 individuals with glycogen s torage disease type 0, one of whom was homozygous and one was compound heterozyg ous for this variant (Ohno 1998 and Soggia 2010). This variant has also been ide ntified in 0.2% (31/16479) of South Asian chromosomes by the Exome Aggregation C onsortium (ExAC, http://exac.broadinstitute.org; dbSNP rs121918419). This nonsen se variant leads to a premature termination codon at position 246, which is pred icted to lead to a truncated or absent protein. Loss of function of the GYS2 gen e is associated with glycogen storage disease type 0. In summary, although addit ional studies are required to fully establish its clinical significance, the p.A rg246X variant is likely pathogenic.
Invitae RCV000017427 SCV000812768 pathogenic Glycogen storage disease due to hepatic glycogen synthase deficiency 2017-08-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg246*) in the GYS2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs121918419, ExAC 0.2%), including at least one homozygous and/or hemizygous individual. This variant has been reported in the homozygous or compound heterozygous state in several individuals affected with glycogen storage disease type 0 (PMID: 9691087, 20051115, 25070466). ClinVar contains an entry for this variant (Variation ID: 16049). Loss-of-function variants in GYS2 are known to be pathogenic (PMID: 9691087). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000017427 SCV000893971 pathogenic Glycogen storage disease due to hepatic glycogen synthase deficiency 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000017427 SCV000914580 pathogenic Glycogen storage disease due to hepatic glycogen synthase deficiency 2018-08-14 criteria provided, single submitter clinical testing The GYS2 c.736C>T (p.Arg246Ter) variant is a stop-gained variant that has been reported in five studies in which it is found in a total of six individuals from five unrelated families affected with the liver presentation of glycogen storage disease type 0 (GSD 0), including three individuals who carried the variant in a homozygous state (including one sibling pair), and in three individuals who carried the variant in a compound heterozygous state (Orho et al. 1998; Bachrach et al. 2002; Soggia et al. 2010; Brown et al. 2015; Kasapkara et al. 2017). The p.Arg246Ter variant was also detected in a heterozygous state in five family members of patients, one of whom was described as glucose intolerant. The variant was absent from 400 control chromosomes and is reported at a frequency of 0.002047 in the South Asian population of the Genome Aggregation Database. There is one homozygote present in the Genome Aggregation Database which can be explained by the variable presentation of liver GSD 0 which may go undetected even in adulthood. Based on the collective evidence, the c.736C>T (p.Arg246Ter) variant is classified as pathogenic for the liver form of glycogen storage disease type 0. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
OMIM RCV000017427 SCV000037699 pathogenic Glycogen storage disease due to hepatic glycogen synthase deficiency 1998-08-01 no assertion criteria provided literature only

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