ClinVar Miner

Submissions for variant NM_016203.4(PRKAG2):c.500C>T (p.Thr167Ile)

gnomAD frequency: 0.00001  dbSNP: rs766578540
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001346875 SCV001541110 uncertain significance Lethal congenital glycogen storage disease of heart 2020-08-16 criteria provided, single submitter clinical testing 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with PRKAG2-related conditions. This variant is present in population databases (rs766578540, ExAC 0.006%). This sequence change replaces threonine with isoleucine at codon 167 of the PRKAG2 protein (p.Thr167Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine.
All of Us Research Program, National Institutes of Health RCV004005208 SCV004818574 uncertain significance Hypertrophic cardiomyopathy 2024-05-14 criteria provided, single submitter clinical testing This missense variant replaces threonine with isoleucine at codon 167 of the PRKAG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 32880476). This variant has been identified in 2/251470 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.
Ambry Genetics RCV004651599 SCV005149145 uncertain significance Cardiovascular phenotype 2024-03-28 criteria provided, single submitter clinical testing The p.T167I variant (also known as c.500C>T), located in coding exon 4 of the PRKAG2 gene, results from a C to T substitution at nucleotide position 500. The threonine at codon 167 is replaced by isoleucine, an amino acid with similar properties. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort (Verdonschot JAJ et al. Circ Genom Precis Med, 2020 Oct;13:476-487). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.

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