ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.1843T>A (p.Ser615Thr) (rs768286281)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183808 SCV000236290 likely pathogenic not provided 2011-08-08 criteria provided, single submitter clinical testing This variant is denoted Ser615Thr (aka S615T) at the protein level and c.1843 T>A at the cDNA level. The Ser615Thr variant in the PKP2 gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. A different amino acid change at the same codon, Ser615Phe, has been reported in association with ARVC and this mutation has been shown to co-segregate with an ARVC phenotype in one family (Gerull et al, 2004; Syrris et al, 2006; Quarta et al, 2011). The Ser615 residue is highly conserved across species and Ser615Thr was not detected in up to 400 alleles from control individuals of Caucasian and African American ancestry tested at GeneDx. However, Ser615Thr is a conservative substitution of one neutral, polar amino acid for another. In summary, while the Ser615Thr variant is a good candidate for a disease-causing mutation, we cannot unequivocally determine whether this variant is a disease-causing mutation or a rare benign variant with the clinical and molecular information available at this time. The variant is found in ARVC panel(s).
Invitae RCV000801922 SCV000941725 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 615 of the PKP2 protein (p.Ser615Thr). The serine residue is highly conserved and there is a small physicochemical difference between serine and threonine. This variant is present in population databases (rs768286281, ExAC 0.001%). This variant has been observed in an individual who suffered sudden unexplained death (PMID: 22019812). ClinVar contains an entry for this variant (Variation ID: 202032). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Ser615 amino acid residue in PKP2. Other variant(s) that disrupt this residue have been observed in individuals with PKP2-related conditions (PMID: 15489853, 23671136, 21606390, Invitae), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.