ClinVar Miner

Submissions for variant NM_016203.4(PRKAG2):c.521C>T (p.Thr174Met)

gnomAD frequency: 0.00021  dbSNP: rs148056866
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Total submissions: 7
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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 RCV000151679 SCV000199975 uncertain significance not specified 2013-10-31 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Thr174Met varia nt in PRKAG2 has not been reported in individuals with cardiomyopathy, but has b een identified in 0.5% (1/192) of Kenyan chromosomes by the 1000 Genomes Project and in 3/4406 African American chromosomes by the NHLBI Exome Sequencing Projec t (http://evs.gs.washington.edu/EVS/; dbSNP rs148056866). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIF T) suggest that the Thr174Met variant may not impact the protein, though this in formation is not predictive enough to rule out pathogenicity. Although this data supports that the Thr174Met variant may be benign, additional studies are neede d to fully assess its clinical significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001087682 SCV000551579 likely benign Lethal congenital glycogen storage disease of heart 2025-01-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620500 SCV000740008 uncertain significance Cardiovascular phenotype 2023-11-21 criteria provided, single submitter clinical testing The p.T174M variant (also known as c.521C>T), located in coding exon 4 of the PRKAG2 gene, results from a C to T substitution at nucleotide position 521. The threonine at codon 174 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in cardiac genetic testing cohorts; however, clinical details were limited and additional cardiac variants were detected in some cases (Seidelmann SB et al. Circ Cardiovasc Genet, 2017 Feb;10:[ePub ahead of print]; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Pottinger TD et al. J Am Heart Assoc, 2020 02;9:e013808). This amino acid position is not well 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001170705 SCV001333299 uncertain significance Cardiomyopathy 2018-01-30 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001170705 SCV001347664 likely benign Cardiomyopathy 2019-11-24 criteria provided, single submitter clinical testing
GeneDx RCV000675710 SCV001787317 uncertain significance not provided 2024-07-02 criteria provided, single submitter clinical testing In silico analysis indicates that this missense variant does not alter protein structure/function; Identified in patients with cardiomyopathy in the published literature (PMID: 32746448, 32009526); This variant is associated with the following publications: (PMID: 32746448, 32009526)
Mayo Clinic Laboratories, Mayo Clinic RCV000675710 SCV000801424 uncertain significance not provided 2017-10-03 no assertion criteria provided clinical testing

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