ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.964G>T (p.Gly322Cys) (rs200069860)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766568 SCV000236212 uncertain significance not provided 2018-05-10 criteria provided, single submitter clinical testing The G322C variant has not been published as a mutation or as a benign polymorphism to our knowledge. The G332C variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The G322C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is class conserved across species. Only one missense mutation in a nearby residue (G328R) has been reported in association with ARVC, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Blueprint Genetics RCV000208208 SCV000264141 uncertain significance Ventricular fibrillation 2015-08-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000251473 SCV000318516 uncertain significance Cardiovascular phenotype 2019-03-13 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV001087213 SCV000545242 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-12-31 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000183732 SCV000747979 uncertain significance not specified 2017-03-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000183732 SCV000918019 uncertain significance not specified 2018-07-30 criteria provided, single submitter clinical testing Variant summary: PKP2 c.964G>T (p.Gly322Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9e-05 in 276374 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PKP2 causing Cardiomyopathy (9e-05 vs 0.0011), allowing no conclusion about variant significance. The variant, c.964G>T, has been reported in the literature in individuals affected with unexplained cardicac arrest (Mellor 2017). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852677 SCV000995385 likely benign Amyloidogenic transthyretin amyloidosis 2019-05-20 criteria provided, single submitter clinical testing
Color RCV001181080 SCV001346156 likely benign Cardiomyopathy 2020-03-05 criteria provided, single submitter clinical testing

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