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

gnomAD frequency: 0.00009  dbSNP: rs121918419

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000017427	SCV000812768	pathogenic	Glycogen storage disorder due to hepatic glycogen synthase deficiency	2023-10-26	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. Loss-of-function variants in GYS2 are known to be pathogenic (PMID: 9691087). This variant is present in population databases (rs121918419, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individuals with glycogen storage disease type 0 (PMID: 9691087, 20051115, 25070466). ClinVar contains an entry for this variant (Variation ID: 16049). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000017427	SCV000893971	pathogenic	Glycogen storage disorder due to hepatic glycogen synthase deficiency	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000017427	SCV000914580	pathogenic	Glycogen storage disorder 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.
Revvity Omics, Revvity	RCV000017427	SCV002024939	pathogenic	Glycogen storage disorder due to hepatic glycogen synthase deficiency	2023-07-03	criteria provided, single submitter	clinical testing
3billion	RCV000017427	SCV002059053	pathogenic	Glycogen storage disorder due to hepatic glycogen synthase deficiency	2022-01-03	criteria provided, single submitter	clinical testing	Stop-gained (nonsense): 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 (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000016049, PMID:9691087). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000354, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx	RCV002251426	SCV002521980	pathogenic	not provided	2022-02-10	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: severely impaired glycogen synthase activity (Orho et al., 1998); This variant is associated with the following publications: (PMID: 25525159, 31589614, 32374048, 20051115, 29961766, 28245189, 30609409, 30487145, 31980526, 9691087)
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251909	SCV002523123	pathogenic	See cases	2021-04-05	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PM3
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000017427	SCV002768259	pathogenic	Glycogen storage disorder due to hepatic glycogen synthase deficiency	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. 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 known to have variable expressivity. Variable clinical phenotypes have been reported in affected individuals within the same family (PMIDs: 18341095, 28245189, 32395408). (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 (98 heterozygotes, 1 homozygote). (SP) 0701 - Other variants resulting in a premature termination codon comparable to the one identified in this case have very strong previous evidence for pathogenicity. At least 10 other NMD-predicted variants have been reported in affected individuals (PMID: 32779500) or as likely pathogenic/pathogenic in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with glycogen synthase deficiency (PMIDs: 12072888, 28245189, 32779500) and as likely pathogenic/pathogenic in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000017427	SCV003933997	pathogenic	Glycogen storage disorder due to hepatic glycogen synthase deficiency	2023-05-23	criteria provided, single submitter	clinical testing	Variant summary: GYS2 c.736C>T (p.Arg246X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, a commonly known mechanism for disease. The variant allele was found at a frequency of 0.00038 in 251426 control chromosomes in the gnomAD database, including 1 homozygote. As the exact prevalence of this disorder is not established, this frequency does not allow conclusions about variant significance. c.736C>T has been reported in the literature as a homozygous or compound heterozygous genotype in multiple individuals affected with Glycogen Storage Disorder Due To Hepatic Glycogen Synthase Deficiency (example, Orho_1998, Bachrach_2002, Soggia_2010, Cakar_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Orho_1998). The most pronounced variant effect results in complete abolishment of normal Glycogen synthase activity in-vitro. The following publications have been ascertained in the context of this evaluation (PMID: 12072888, 32374048, 33502066, 9691087, 20051115). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003944826	SCV004766207	pathogenic	GYS2-related disorder	2023-11-27	criteria provided, single submitter	clinical testing	The GYS2 c.736C>T variant is predicted to result in premature protein termination (p.Arg246*). This variant has been reported in the homozygous and compound heterozygous state in multiple individuals with glycogen storage disease (see for example, Figure 1, Orho et al. 1998. PubMed ID: 9691087; Bachrach et al. 2002. PubMed ID: 12072888; Figure 1, Soggia et al. 2010. PubMed ID: 20051115). This variant is reported in 0.21% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in GYS2 are expected to be pathogenic. This variant is interpreted as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000017427	SCV004809852	pathogenic	Glycogen storage disorder due to hepatic glycogen synthase deficiency	2024-04-04	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000017427	SCV005044800	pathogenic	Glycogen storage disorder due to hepatic glycogen synthase deficiency		criteria provided, single submitter	clinical testing	The stop gained c.736C>Tp.Arg246Ter variant in the GYS2 gene has been reported previously in homozygous state in individuals affected with Glycogen storage disease 0, liver Brown, Laurie M et al., 2015. This variant is reported with the allele frequency 0.03% in the gnomAD Exomes and novel in 1000 Genomes. It is submitted to ClinVar as Likely Pathogenic/ Pathogenic multiple submissions. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The nucleotide change c.736C>T in GYS2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000017427	SCV000037699	pathogenic	Glycogen storage disorder due to hepatic glycogen synthase deficiency	1998-08-01	no assertion criteria provided	literature only