Submissions for variant NM_016203.4(PRKAG2):c.997T>G (p.Ser333Ala)

gnomAD frequency: 0.00001  dbSNP: rs775005432

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770262	SCV000901694	uncertain significance	Cardiomyopathy	2016-04-22	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000788369	SCV000927453	uncertain significance	not provided	2017-10-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000770262	SCV001357678	uncertain significance	Cardiomyopathy	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces serine with alanine at codon 333 of the PRKAG2 protein. Computational prediction suggests that this variant may have a 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, who also carried another pathogenic variant in the MYH7 gene (PMID: 31110529). This variant has been identified in 3/250994 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001320685	SCV001511480	uncertain significance	Lethal congenital glycogen storage disease of heart	2023-11-29	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 333 of the PRKAG2 protein (p.Ser333Ala). This variant is present in population databases (rs775005432, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PRKAG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 626749). 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. 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.
Fulgent Genetics, Fulgent Genetics	RCV002487572	SCV002786288	uncertain significance	Lethal congenital glycogen storage disease of heart; Hypertrophic cardiomyopathy 6; Wolff-Parkinson-White pattern	2021-10-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004027224	SCV003906511	uncertain significance	Cardiovascular phenotype	2023-02-22	criteria provided, single submitter	clinical testing	The c.997T>G (p.S333A) alteration is located in exon 8 (coding exon 8) of the PRKAG2 gene. This alteration results from a T to G substitution at nucleotide position 997, causing the serine (S) at amino acid position 333 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV003999936	SCV004842232	uncertain significance	Hypertrophic cardiomyopathy	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces serine with alanine at codon 333 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). 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 been reported in an individual affected with hypertrophic cardiomyopathy, who also carried another pathogenic variant in the MYH7 gene (PMID: 31110529). This variant has been identified in 3/250994 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.