ClinVar Miner

Submissions for variant NM_016203.4(PRKAG2):c.865G>A (p.Val289Ile)

dbSNP: rs397517282
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000038958 SCV000062636 uncertain significance not specified 2013-02-06 criteria provided, single submitter clinical testing The Val289Ile variant in PRKAG2 has not been reported in the literature and was absent from in large European American and African American populations by the N HLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS), which increase s the likelihood that the variant is pathogenic. This variant has been identifie d by our laboratory in 1 Caucasian individual with HCM who also carried a pathog enic MYBPC3 variant. The variant occurs in the first base of the exon and though variants in this position can sometimes affect splicing, computational tools do not predict an effect. Valine (Val) at position 289 is highly conserved in mamm als and across evolutionarily distant species, though computational analyses (bi ochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, additional i nformation is needed to fully assess the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health RCV001184219 SCV001350159 uncertain significance Cardiomyopathy 2024-01-02 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 289 of the PRKAG2 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has been identified in 1/250708 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 RCV001852815 SCV002140249 uncertain significance Lethal congenital glycogen storage disease of heart 2022-10-11 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 289 of the PRKAG2 protein (p.Val289Ile). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 45736). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). This variant is present in population databases (rs397517282, gnomAD 0.0009%).
GeneDx RCV002460899 SCV002757341 uncertain significance not provided 2022-11-23 criteria provided, single submitter clinical testing Identified in a patient with hypertrophic cardiomyopathy, but additional clinical information was not included (Walsh R et al., 2017); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257)
Fulgent Genetics, Fulgent Genetics RCV002496622 SCV002792770 uncertain significance Lethal congenital glycogen storage disease of heart; Hypertrophic cardiomyopathy 6; Wolff-Parkinson-White pattern 2021-10-27 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003996426 SCV004842242 uncertain significance Hypertrophic cardiomyopathy 2023-10-06 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 289 of the PRKAG2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/250708 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.

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