Submissions for variant NM_016203.4(PRKAG2):c.698C>G (p.Ala233Gly)

gnomAD frequency: 0.00015  dbSNP: rs201240745

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038955	SCV000062633	uncertain significance	not specified	2012-11-14	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Ala233Gly varia nt in PRKAG2 has not been reported in the literature, but has been identified in one infant with unspecified cardiomyopathy previously tested by our laboratory. This variant is located outside of the CBS domain, where all pathogenic PRKAG2 mutations have been identified to date (Oliveira 2003), raising the possibility that it may be tolerated. Computational analyses (biochemical amino acid propert ies, conservation, AlignGVGD, PolyPhen2, and SIFT) also suggest that the Ala233G ly variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, additional information is needed to fully assess the clinical significance of the Ala233Gly variant.
GeneDx	RCV000588424	SCV000581876	uncertain significance	not provided	2022-10-20	criteria provided, single submitter	clinical testing	Reported in a patient with hypoplastic left heart and left ventricular noncompaction in published literature (Ritter et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31527676)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588424	SCV000699420	likely benign	not provided	2017-03-28	criteria provided, single submitter	clinical testing	Variant summary: The PRKAG2 c.698C>G (p.Ala233Gly) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant. This variant was found in 17/77136 control chromosomes, predominantly observed in the European subpopulation at a frequency of 0.000371 (17/45836). This frequency is about 15 times the estimated maximal expected allele frequency of a pathogenic PRKAG2 variant (0.000025), suggesting this is likely a benign polymorphism found primarily in the populations of European origin. One clinical diagnostic laboratory identified this variant in one infant with unspecified cardiomyopathy and classified this variant as uncertain significance without additional evidence for independent review. One reputable database classified this variant as "unlikely to be pathogenic". Taken together, this variant is classified as likely benign.
Invitae	RCV000699614	SCV000828333	likely benign	Lethal congenital glycogen storage disease of heart	2024-01-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588424	SCV000892811	likely benign	not provided	2023-05-01	criteria provided, single submitter	clinical testing	PRKAG2: BP4
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769246	SCV000900622	uncertain significance	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769246	SCV000904655	likely benign	Cardiomyopathy	2019-11-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001161541	SCV001323428	uncertain significance	Wolff-Parkinson-White pattern	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001161542	SCV001323429	uncertain significance	Hypertrophic cardiomyopathy 6	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001199301	SCV001370379	uncertain significance	See cases	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256863	SCV001433354	uncertain significance	Hypertrophic cardiomyopathy 1	2019-11-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162342	SCV003902557	uncertain significance	Cardiovascular phenotype	2023-03-03	criteria provided, single submitter	clinical testing	The p.A233G variant (also known as c.698C>G), located in coding exon 5 of the PRKAG2 gene, results from a C to G substitution at nucleotide position 698. The alanine at codon 233 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in an acute heart failure in infancy cohort; however, clinical details were limited (Ritter A et al. Genet Med, 2020 Feb;22:423-426). This amino acid position is well 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.