ClinVar Miner

Submissions for variant NM_016203.4(PRKAG2):c.147C>A (p.Asp49Glu)

dbSNP: rs761196275
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001294807 SCV001483702 uncertain significance Lethal congenital glycogen storage disease of heart 2022-08-09 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 49 of the PRKAG2 protein (p.Asp49Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PRKAG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 998887). 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) performed at Invitae indicates that this missense variant is not expected to disrupt PRKAG2 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
GeneDx RCV003313208 SCV004012720 uncertain significance not provided 2023-01-10 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
New York Genome Center RCV003448391 SCV004176210 uncertain significance Hypertrophic cardiomyopathy 6 2023-07-27 criteria provided, single submitter clinical testing The c.147C>A, p.(Asp49Glu) variant identified in the PRKAG2 gene is located on exon 2 of this 16-exon gene and substitutes an Aspartic Acid for a Glutamic acid at amino acid position 49 of the encoded protein. This variant is observed in 3 heterozygous alleles (with 0 homozygotes) in population databases (gnomAD v2.1.1, gnomADv3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. This variant has been deposited on ClinVar as a Variant of Uncertain Significance (ClinVar: 998887) by two submitters. To our current knowledge this variant has not been reported in affected individuals in the literature. In silico algorithms are inconclusive of the damaging effect of this variant on protein function (REVEL score: 0.481). Functional studies are not available to provide more information about the variant’s damaging effect. Based on available evidence this c.147C>A, p.(Asp49Glu) variant identified in the PRKAG2 gene is classified as a Variant of Uncertain Significance.

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