Submissions for variant NM_016203.4(PRKAG2):c.224G>C (p.Gly75Ala)

dbSNP: rs199963585

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000267792	SCV000467660	uncertain significance	Wolff-Parkinson-White pattern	2018-01-13	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	RCV000377613	SCV000467662	uncertain significance	Hypertrophic cardiomyopathy 6	2018-01-13	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.
Color Diagnostics, LLC DBA Color Health	RCV001187909	SCV001354827	uncertain significance	Cardiomyopathy	2023-03-29	criteria provided, single submitter	clinical testing	This variant is located in 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 a Japanese individual affected with myocyte disarray in the heart (PMID: 30959811). This variant has also been identified in 11/241710 chromosomes (11/18080 East Asian 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.
Invitae	RCV001488798	SCV001693323	likely benign	Lethal congenital glycogen storage disease of heart	2023-11-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002429323	SCV002729353	uncertain significance	Cardiovascular phenotype	2022-10-06	criteria provided, single submitter	clinical testing	The p.G75A variant (also known as c.224G>C), located in coding exon 3 of the PRKAG2 gene, results from a G to C substitution at nucleotide position 224. The glycine at codon 75 is replaced by alanine, an amino acid with similar properties. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235198	SCV003933948	likely benign	not specified	2023-05-16	criteria provided, single submitter	clinical testing	Variant summary: PRKAG2 c.224G>C (p.Gly75Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 241710 control chromosomes. The observed variant frequency is approximately 3.64 fold of the estimated maximal expected allele frequency for a pathogenic variant in PRKAG2 causing Hypertrophic Cardiomyopathy With Wolff-Parkinson-White phenotype (1.3e-05), strongly suggesting that the variant is benign. c.224G>C has been reported in the literature in individuals affected with myocyte disarray (Hata_2019). This report does not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy With Wolff-Parkinson-White. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30959811). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One submitter classified as likely benign while three classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign.