Submissions for variant NM_016203.4(PRKAG2):c.298G>A (p.Gly100Ser)

gnomAD frequency: 0.00144  dbSNP: rs79474211

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038934	SCV000053043	likely benign	not specified	2018-03-06	criteria provided, single submitter	clinical testing	Variant summary: PRKAG2 c.298G>A (p.Gly100Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0068 in 276670 control chromosomes in the gnomAD database, including 44 homozygotes. The observed variant frequency is approximately 270.79 fold of the estimated maximal expected allele frequency for a pathogenic variant in PRKAG2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.298G>A has been reported in the literature in individuals affected with Cardiomyopathy (Zhang_2013, Zhao_2017), however co-occurrences with other pathogenic variant(s) have been reported (MYBPC3 c.3624delC , p.Lys1209Serfs ; TNNT2 c.274C>T, p.Arg92Trp), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity (Zhang_2013). Multiple clinical diagnostic laboratories have classified the variant as "likely benign/benign." Based on the evidence outlined above, the variant was classified as likely benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038934	SCV000062612	benign	not specified	2012-07-24	criteria provided, single submitter	clinical testing	Gly100Ser in exon 3 of PRKAG2: Although this variant changes an amino acid, it i s present at high frequency in Asian populations (2-7%, 1000 Genomes data). This is consistent with its high frequency in Asian probands tested by our laborator y. In addition, this variant is outside of the CBS domain (residues 277-555) wh ere all pathogenic variants in PRKAG2 have so far been identified. In summary, t he variants frequency in the general population suggests that is not disease cau sing in isolation though a modifying effect cannot be ruled out.
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490302	SCV000267461	uncertain significance	Wolff-Parkinson-White pattern	2016-03-18	criteria provided, single submitter	reference population
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229228	SCV000290208	benign	Lethal congenital glycogen storage disease of heart	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000247427	SCV000317971	benign	Cardiovascular phenotype	2014-12-08	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV000314869	SCV000467652	likely benign	Hypertrophic cardiomyopathy 6	2018-12-12	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000490302	SCV000467653	likely benign	Wolff-Parkinson-White pattern	2018-12-12	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Eurofins Ntd Llc (ga)	RCV000038934	SCV000700586	benign	not specified	2017-03-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776032	SCV000910620	benign	Cardiomyopathy	2018-03-19	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000776032	SCV001333301	likely benign	Cardiomyopathy	2023-06-20	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001258286	SCV001435213	benign	Renal cysts and diabetes syndrome		criteria provided, single submitter	research	The heterozygous p.Gly100Ser variant in PRKAG2 has been identified in 12 Chinese individuals with Wolff-Parkinson-White syndrome, conduction system disease, and/or hypertrophic cardiomyopathy, segregated with disease in 12 relatives from 1 family (PMID: 23778007), but has also been identified in >3% of South Asian chromosomes and 30 homozygotes by ExAC (http://gnomad.broadinstitute.org/). Functional studies with zebrafish provide some evidence that the p.Gly100Ser variant may slightly impact protein function (PMID: 23992123). However, these types of assays may not accurately represent biological function. This variant is not in the same domain as all other previously identified pathogenic variants, suggesting that this variant may be benign (PMID: 23778007). In summary, this variant meets criteria to be classified as benign for autosomal dominant PRKAG2 cardiac syndrome.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001529977	SCV001472065	benign	not provided	2021-09-13	criteria provided, single submitter	clinical testing
GeneDx	RCV001529977	SCV001827697	benign	not provided	2018-12-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28498465, 28801758, 28138913, 23778007, 27082122, 27153395, 27535533, 27884173, 25637381, 23992123)
CeGaT Center for Human Genetics Tuebingen	RCV001529977	SCV002586209	benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	PRKAG2: BS1, BS2
CSER _CC_NCGL, University of Washington	RCV000148737	SCV000190473	likely benign	PRKAG2 cardiac syndrome	2014-06-01	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529977	SCV001744396	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000038934	SCV001917837	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000038934	SCV001932655	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000038934	SCV001952543	benign	not specified		no assertion criteria provided	clinical testing