Submissions for variant NM_016203.4(PRKAG2):c.712G>A (p.Ala238Thr)

gnomAD frequency: 0.00051  dbSNP: rs200736454

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000786197	SCV000208929	likely benign	not provided	2020-12-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001088403	SCV000290216	likely benign	Lethal congenital glycogen storage disease of heart	2025-01-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000622232	SCV000739920	likely benign	Cardiovascular phenotype	2018-04-24	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170703	SCV001333297	benign	Cardiomyopathy	2019-02-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170703	SCV001339602	likely benign	Cardiomyopathy	2019-08-22	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 238 of the PRKAG2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 27/192420 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786197	SCV000924907	uncertain significance	not provided	2016-06-21	no assertion criteria provided	provider interpretation	Given the lack of case data and relatively high frequency in ethnicity-matched controls we consider this variant to be uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has not been reported in the literature. We have seen this variant in an individual with LVNC. The Invitae report notes: The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. Please note that this site is covered in fewer than 80% of the individuals in Exac, and may represent a low quality site. The variant was reported online in 12 of 40,075 (0.2%) individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 4/2016). Specifically, the variant was observed in 12 of 2461 (0.4%) people of African descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease
PreventionGenetics, part of Exact Sciences	RCV004734751	SCV005350699	likely benign	PRKAG2-related disorder	2024-08-12	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).