ClinVar Miner

Submissions for variant NM_016203.4(PRKAG2):c.298G>A (p.Gly100Ser) (rs79474211)

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Total submissions: 18
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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, Partners HealthCare 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
Invitae RCV000229228 SCV000290208 benign Glycogen storage disease of heart, lethal congenital 2020-12-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000247427 SCV000317971 benign Cardiovascular phenotype 2014-12-08 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Illumina Clinical Services Laboratory,Illumina RCV000314869 SCV000467652 likely benign Familial 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 Clinical Services Laboratory,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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000038934 SCV000700586 benign not specified 2017-03-30 criteria provided, single submitter clinical testing
Color Health, Inc 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 2019-02-20 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute 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 RCV001285604 SCV001472065 benign none provided 2019-12-15 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)
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
Human Genetics - Radboudumc,Radboudumc RCV000038934 SCV001952543 benign not specified no assertion criteria provided clinical testing

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