Submissions for variant NM_016203.4(PRKAG2):c.111T>A (p.Ile37=)

gnomAD frequency: 0.00259  dbSNP: rs144426409

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038906	SCV000062584	benign	not specified	2012-03-01	criteria provided, single submitter	clinical testing	Ile37Ile in exon 1 of PRKAG2: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and has been identified in 0.5% (33/7020) of European American chromosomes from a broad population by t he NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs144 426409).
Eurofins Ntd Llc (ga)	RCV000038906	SCV000224570	benign	not specified	2014-11-21	criteria provided, single submitter	clinical testing
Invitae	RCV000228988	SCV000290199	benign	Lethal congenital glycogen storage disease of heart	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000244616	SCV000318062	likely benign	Cardiovascular phenotype	2016-07-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV000372444	SCV000467682	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.
Illumina Laboratory Services, Illumina	RCV000277990	SCV000467683	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770266	SCV000901698	benign	Cardiomyopathy	2017-10-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000770266	SCV000910836	benign	Cardiomyopathy	2018-03-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038906	SCV000918092	benign	not specified	2018-05-29	criteria provided, single submitter	clinical testing	Variant summary: PRKAG2 c.111T>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0023 in 271072 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 94-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in PRKAG2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.111T>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Multiple ClinVar submissions from clinical diagnostic laboratories cite the variant predominantly as "likely benign/benign" (2x) and once as "uncertain significance." Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV001529843	SCV001746939	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	PRKAG2: BP4, BP7, BS1
GeneDx	RCV001529843	SCV001891885	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001529843	SCV002049109	benign	not provided	2023-10-14	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529843	SCV001744020	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000038906	SCV001925945	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000038906	SCV001927781	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000038906	SCV001955860	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000038906	SCV001968379	benign	not specified		no assertion criteria provided	clinical testing
Cohesion Phenomics	RCV003125867	SCV003803054	benign	Hypertrophic cardiomyopathy	2022-09-29	no assertion criteria provided	clinical testing