Submissions for variant NM_016203.4(PRKAG2):c.1114G>A (p.Asp372Asn)

gnomAD frequency: 0.00005  dbSNP: rs760826751

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000560606	SCV000640338	uncertain significance	Lethal congenital glycogen storage disease of heart	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 372 of the PRKAG2 protein (p.Asp372Asn). This variant is present in population databases (rs760826751, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of PRKAG2-related conditions (PMID: 30847666, 35600473). ClinVar contains an entry for this variant (Variation ID: 465337). 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.
Ambry Genetics	RCV000620896	SCV000737033	uncertain significance	Cardiovascular phenotype	2024-05-17	criteria provided, single submitter	clinical testing	The p.D372N variant (also known as c.1114G>A), located in coding exon 11 of the PRKAG2 gene, results from a G to A substitution at nucleotide position 1114. The aspartic acid at codon 372 is replaced by asparagine, an amino acid with highly similar properties. This variant was detected in an arrhythmia genetic testing cohort; however, clinical details were limited (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This variant was also reported in a family with dilated cardiomyopathy (DCM), who also had alterations in other cardiac-related genes (Huang W et al. Front Cardiovasc Med, 2022 May;9:822150). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV001158332	SCV001319965	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	RCV001165047	SCV001327214	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	RCV001177891	SCV001342190	uncertain significance	Cardiomyopathy	2023-02-28	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 372 of the PRKAG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 arrhythmia (PMID: 30847666 ). This variant has been identified in 5/251332 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	RCV001529850	SCV001780330	uncertain significance	not provided	2021-02-04	criteria provided, single submitter	clinical testing	Observed in a patient with arrhythmia (van Lint et al., 2019); however, additional clinical information was not provided; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 465337; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30847666)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001177891	SCV002043485	uncertain significance	Cardiomyopathy	2020-08-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387879	SCV004099817	uncertain significance	not specified	2023-09-13	criteria provided, single submitter	clinical testing	Variant summary: PRKAG2 c.1114G>A (p.Asp372Asn) results in a conservative amino acid change located in the CBS domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251332 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1114G>A has been reported in the literature in an individual with arrhythmia (van Lint_2019) and in two individuals with dilated cardiomyopathy (DCM) combined with multifocal ectopic Purkinje-related premature contractions (MEPPC) who were also suspected of PRKAG2 syndrome and suffered sudden deaths, however they also harbored a putatively pathogenic variant in SCN5A which was found in other family members with DCM and MEPPC, and their father who also carried the variant of interest (but not the variant in SCN5A) was unaffected (Huang_2022). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35600473, 30847666). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003999158	SCV004842228	uncertain significance	Hypertrophic cardiomyopathy	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 372 of the PRKAG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 arrhythmia (PMID: 30847666 ). This variant has been identified in 5/251332 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.
Clinical Genomics Laboratory, Stanford Medicine	RCV001165047	SCV005062007	uncertain significance	Hypertrophic cardiomyopathy 6	2021-07-23	criteria provided, single submitter	clinical testing	The p.Asp372Asn variant in the PRKAG2gene has been previously reported in an individual with unknown arrhythmia as part of an inherited cardiac disease cohort undergoing arrhythmia and cardiomyopathy gene panel testing (van Lint et al., 2019). This variant has been identified in 5/251,332 chromosomes by the Genome AggregationDatabase (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, it has not been observed at a frequency high enough to rule out pathogenicity. The aspartic acid at position 372 is highly evolutionarily conserved. Computational tools predict that the p.Asp372Asn variant is deleterious; however, the accuracy of in silicoalgorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Asp372Asn variant is uncertain. Additional information is needed to resolve the significance of this variant.[ACMG evidence codes used: PM2; PP3]
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529850	SCV001744033	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001529850	SCV001917535	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001529850	SCV001927046	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001529850	SCV001966890	uncertain significance	not provided		no assertion criteria provided	clinical testing