Submissions for variant NM_016203.4(PRKAG2):c.1295C>T (p.Thr432Met)

gnomAD frequency: 0.00001  dbSNP: rs760879406

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001763022	SCV001989103	uncertain significance	not provided	2021-02-11	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32646569)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861058	SCV002163579	uncertain significance	Lethal congenital glycogen storage disease of heart	2022-12-31	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PRKAG2 protein function. ClinVar contains an entry for this variant (Variation ID: 1303564). This missense change has been observed in individual(s) with PRKAG2-related conditions (PMID: 32646569). This variant is present in population databases (rs760879406, gnomAD 0.002%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 432 of the PRKAG2 protein (p.Thr432Met).
Ambry Genetics	RCV002386517	SCV002692867	uncertain significance	Cardiovascular phenotype	2020-01-28	criteria provided, single submitter	clinical testing	The p.T432M variant (also known as c.1295C>T), located in coding exon 12 of the PRKAG2 gene, results from a C to T substitution at nucleotide position 1295. The threonine at codon 432 is replaced by methionine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002506760	SCV002815203	uncertain significance	Lethal congenital glycogen storage disease of heart; Hypertrophic cardiomyopathy 6; Wolff-Parkinson-White pattern	2021-09-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004008987	SCV004815701	uncertain significance	Hypertrophic cardiomyopathy	2024-05-17	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 432 of the PRKAG2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 30847666) and in another individual affected with PRKAG2-related disorders (PMID: 32646569). This variant has been identified in 2/251468 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.