Submissions for variant NM_016203.4(PRKAG2):c.428C>T (p.Ser143Leu)

gnomAD frequency: 0.00001  dbSNP: rs397517271

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001064983	SCV001229921	uncertain significance	Lethal congenital glycogen storage disease of heart	2022-11-17	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) performed at Invitae indicates that this missense variant is not expected to disrupt PRKAG2 protein function. ClinVar contains an entry for this variant (Variation ID: 45718). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257, 32150461). This variant is present in population databases (rs397517271, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 143 of the PRKAG2 protein (p.Ser143Leu).
Color Diagnostics, LLC DBA Color Health	RCV001182264	SCV001347657	uncertain significance	Cardiomyopathy	2023-05-18	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 143 of the PRKAG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least two individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 32150461). This variant has been identified in 5/251284 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.
GeneDx	RCV001569922	SCV001794092	uncertain significance	not provided	2019-08-19	criteria provided, single submitter	clinical testing	Reported in association with hypertrophic cardiomyopathy (Walsh et al., 2017); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32150461, 27532257)
All of Us Research Program, National Institutes of Health	RCV003996420	SCV004842298	uncertain significance	Hypertrophic cardiomyopathy	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 143 of the PRKAG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). 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 5/251284 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038940	SCV000062618	uncertain significance	not specified	2008-10-01	no assertion criteria provided	clinical testing