ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.2420C>T (p.Thr807Met)

gnomAD frequency: 0.00002  dbSNP: rs146118033
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Total submissions: 5
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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 RCV000038213 SCV000061881 uncertain significance not specified 2018-05-26 criteria provided, single submitter clinical testing The p.Thr851Met variant in PKP2 has been identified by our laboratory in 2 Cauca sian individuals with ARVC one of whom carried a disease-causing frameshift vari ant in the same gene. This variant has also been identified in 5/25792 Finnish c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org; dbSNP rs1461180033). Computational prediction tools and conservation an alysis suggest that the p.Thr851Met variant may not impact the protein, though t his information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Thr851Met variant is uncertain. ACMG/AMP crit eria applied: BP4.
Invitae RCV000692466 SCV000820291 uncertain significance Arrhythmogenic right ventricular dysplasia 9 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 851 of the PKP2 protein (p.Thr851Met). This variant is present in population databases (rs146118033, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PKP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 45072). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Color Diagnostics, LLC DBA Color Health RCV001181339 SCV001346465 uncertain significance Cardiomyopathy 2023-05-02 criteria provided, single submitter clinical testing This missense variant replaces threonine with methionine at codon 851 of the PKP2 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 14/282856 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.
GeneDx RCV001588851 SCV001814422 uncertain significance not provided 2021-02-25 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 45072; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function
Ambry Genetics RCV002426567 SCV002742957 uncertain significance Cardiovascular phenotype 2023-01-03 criteria provided, single submitter clinical testing The p.T851M variant (also known as c.2552C>T), located in coding exon 13 of the PKP2 gene, results from a C to T substitution at nucleotide position 2552. The threonine at codon 851 is replaced by methionine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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