Submissions for variant NM_016203.4(PRKAG2):c.946+3A>G

gnomAD frequency: 0.00041  dbSNP: rs376173303

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001721012	SCV000208947	likely benign	not provided	2020-10-28	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000216046	SCV000272337	uncertain significance	not specified	2015-11-09	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The c.946+3A>G vari ant in PRKAG2 has not been previously reported in individuals with cardiomyopath y, but has been identified in 0.15% (14/9194) of African chromosomes by the Exom e Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs37617330 3). This variant is located in the 5' splice region. Computational tools do not suggest an impact to splicing. However, this information is not predictive enoug h to rule out pathogenicity. In summary, while the clinical significance of the c.946+3A>G variant is uncertain, these data suggest that it is more likely to be benign.
Invitae	RCV000475665	SCV000551574	likely benign	Lethal congenital glycogen storage disease of heart	2023-11-10	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170702	SCV001333296	benign	Cardiomyopathy	2017-11-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170702	SCV001355402	benign	Cardiomyopathy	2019-01-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000216046	SCV001437444	benign	not specified	2020-09-24	criteria provided, single submitter	clinical testing	Variant summary: PRKAG2 c.946+3A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00012 in 250172 control chromosomes. The observed variant frequency is approximately 9.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in PRKAG2 causing Hypertrophic Cardiomyopathy With Wolff-Parkinson-White phenotype (1.3e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.946+3A>G in individuals affected with Hypertrophic Cardiomyopathy With Wolff-Parkinson-White and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=2, benign, n=2, VUS, n=1). Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV002444660	SCV002683046	likely benign	Cardiovascular phenotype	2019-01-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.