Submissions for variant NM_016203.4(PRKAG2):c.325T>G (p.Ser109Ala)

gnomAD frequency: 0.00025  dbSNP: rs139579816

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038937	SCV000062615	uncertain significance	not specified	2015-08-13	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Ser109Ala var iant in PRKAG2 has been identified in 8/10308 of African chromosomes by the Exom e Aggregation Consortium (ExAC, http://exac.broadinstitute.org; rs139579816). Th is variant has been identified by our laboratory in 3 individuals (1 Black infan t with HCM, 1 Black teenager with RCM/LVNC, and 1 adult of unspecified ethnicity with DCM); however, it was not present in an affected sibling of the infant wit h HCM and was identified in the unaffected mother, both of whom carried another variant of unknown significance in another gene. This variant is located outside the CBS domain region where all pathogenic PRKAG2 variants have been identified to date (Oliveira 2003), reducing the likelihood that it is disease causing. Co mputational prediction tools and conservation analysis also suggest that it may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Ser109A la variant is uncertain, these data suggest that it is more likely to be benign.
GeneDx	RCV000589928	SCV000208978	likely benign	not provided	2019-12-11	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589928	SCV000699418	likely benign	not provided	2016-09-19	criteria provided, single submitter	clinical testing	Variant summary: The PRKAG2 c.325T>G (p.Ser109Ala) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant. This variant is located outside the CBS domain region where pathogenic PRKAG2 variants have been known to cluster (InterPro, Oliveira 2003), reducing the likelihood that it is disease causing. This variant was found in 8/120812 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0007761 (8/10308). This frequency is about 31 times the estimated maximal expected allele frequency of a pathogenic PRKAG2 variant (0.000025), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. This variant has been found in multiple patients with cardiomyopathy from published (Kindel_2012) as well as unpublished (LMM-PH) sources. The variant did not cosegregate with disease in a family (LMM-PH). Two clinical diagnostic laboratories have classified this variant as uncertain significance. Taken together, this variant is classified as likely benign.
Invitae	RCV001079478	SCV000830773	likely benign	Lethal congenital glycogen storage disease of heart	2024-01-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001177609	SCV001341848	likely benign	Cardiomyopathy	2021-01-27	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224125	SCV003920352	uncertain significance	Lethal congenital glycogen storage disease of heart; Hypertrophic cardiomyopathy 6; Wolff-Parkinson-White pattern	2021-03-30	criteria provided, single submitter	clinical testing	PRKAG2 NM_016203.3 exon 3 p.Ser109Ala (c.325T>G): This variant has been reported in the literature in at least one individual with HCM (Kindel 2012 PMID:22555271). This variant is also present in 0.08% (22/24932) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/7-151478379-A-C) and is present in ClinVar (Variation ID:45715). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Ambry Genetics	RCV004017325	SCV004849238	likely benign	Cardiovascular phenotype	2019-11-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.