ClinVar Miner

Submissions for variant NM_016203.4(PRKAG2):c.1475T>A (p.Ile492Asn)

gnomAD frequency: 0.00001  dbSNP: rs186114650
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208512 SCV000264154 uncertain significance Primary familial hypertrophic cardiomyopathy 2015-08-10 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000777947 SCV000914045 uncertain significance Cardiomyopathy 2023-02-22 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with asparagine at codon 492 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257), in a fetus affected with unexplained intrauterine fetal death (PMID: 33762593), and in an individual affected with sudden unexplained death (PMID: 33895855). This variant has been identified in 8/251486 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 RCV001248475 SCV001421963 uncertain significance Lethal congenital glycogen storage disease of heart 2023-11-19 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 492 of the PRKAG2 protein (p.Ile492Asn). This variant is present in population databases (rs186114650, gnomAD 0.005%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 222771). 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 RCV002500669 SCV002806737 uncertain significance Lethal congenital glycogen storage disease of heart; Hypertrophic cardiomyopathy 6; Wolff-Parkinson-White pattern 2021-09-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV003165511 SCV003855210 uncertain significance Cardiovascular phenotype 2023-01-31 criteria provided, single submitter clinical testing The p.I492N variant (also known as c.1475T>A), located in coding exon 14 of the PRKAG2 gene, results from a T to A substitution at nucleotide position 1475. The isoleucine at codon 492 is replaced by asparagine, an amino acid with dissimilar properties. This alteration has been reported in cardiomyopathy cohorts and an intrauterine death cohort; however, clinical details were limited and additional cardiac variants were detected in some cases (Walsh R et al. Genet Med, 2017 Feb;19:192-203; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Muin DA et al. Sci Rep, 2021 Mar;11:6737). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV001699159 SCV003930230 uncertain significance not provided 2023-05-30 criteria provided, single submitter clinical testing Reported in one patient with hypertrophic cardiomyopathy in the published literature, however, detailed clinical information was not provided (Walsh et al., 2017); 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: 27532257)
All of Us Research Program, National Institutes of Health RCV003997688 SCV004842209 uncertain significance Hypertrophic cardiomyopathy 2024-01-03 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with asparagine at codon 492 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257), in a fetus affected with unexplained intrauterine fetal death (PMID: 33762593), and in an individual affected with sudden unexplained death (PMID: 33895855). This variant has been identified in 8/251486 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 Genetics, Academic Medical Center RCV001699159 SCV001923804 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001699159 SCV001966887 uncertain significance not provided no assertion criteria provided clinical testing

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