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.
Labcorp Genetics (formerly Invitae), Labcorp	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: 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.