Submissions for variant NM_016203.4(PRKAG2):c.1703C>T (p.Thr568Met)

gnomAD frequency: 0.00004  dbSNP: rs540525001

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766639	SCV000208931	uncertain significance	not provided	2016-12-12	criteria provided, single submitter	clinical testing	The T568M variant of uncertain significance in the PRKAG2 gene has not been published as pathogenic or been reported as benign to our knowledge. The T568M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, the T568M variant affects the second to last residue of the protein at a position that is not conserved across species, and 2/3 in silico algorithms predict this variant likely does not alter the protein structure/function. Furthermore, the Exome Aggregation Consortium (ExAC) reports T568M was observed in 8/16,512 alleles from individuals of South Asian background and 4/66,740 alleles from individuals of European (Non-Finnish) background.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000686461	SCV000813980	likely benign	Lethal congenital glycogen storage disease of heart	2024-11-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001189153	SCV001356379	likely benign	Cardiomyopathy	2019-11-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399577	SCV002710448	uncertain significance	Cardiovascular phenotype	2022-12-19	criteria provided, single submitter	clinical testing	The p.T568M variant (also known as c.1703C>T), located in coding exon 16 of the PRKAG2 gene, results from a C to T substitution at nucleotide position 1703. The threonine at codon 568 is replaced by methionine, an amino acid with similar properties. This variant has been detected in an individual with hypertrophic cardiomyopathy (HCM) and in an individual from a cohort undergoing genetic testing for HCM (Walsh R et al. Genet. Med., 2017 02;19:192-203; Manhas A et al. Stem Cell Res. 2022 May;61:102774). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223882	SCV000280426	uncertain significance	not specified	2013-12-30	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Thr568Met (c.1703C>T) in PRKAG2 This variant is novel. It has not been reported in association with HCM in peer reviewed publications. This is a non-conservative amino acid change with a neutral, polar Threonine replaced with a non-polar Methionine. Conservation analysis indicates that methionine is not conserved at this position across species and in silico analysis predicts the amino acid change to be benign to protein function. It is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6,000 Caucasian and African American individuals (as of July 2012). General population data matching the patient’s ancestry is not available.