ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.1130T>C (p.Ile377Thr) (rs397516985)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038148 SCV000061814 uncertain significance not specified 2012-05-25 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Ile377Thr v ariant (PKP2) has not been reported in the literature nor previously identified by our laboratory. Computational analyses (biochemical amino acid properties, co nservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Ile377Thr variant m ay impact the protein, though this information is not predictive enough to deter mine pathogenicity. This variant has not been identified in large and broad popu lations by the NHBLI Exome Sequencing Project (http://evs.gs.washington.edu/EVS) . Although computational predictions and absence in the general population suppo rt that the Ile377Thr variant may be pathogenic, additional studies are needed t o fully assess its clinical significance.
GeneDx RCV000766569 SCV000236214 uncertain significance not provided 2015-06-11 criteria provided, single submitter clinical testing p.Ile377Thr (ATA>ACA): c.1130 T>C in exon 4 of the PKP2 gene (NM_004572.3). The Ile377Thr variant in the PKP2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The Ile377Thr variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Ile377Thr results in a semi-conservative amino acid substitution of a non-polar Isoleucine with a polar Threonine at a position that is well conserved across species. In silico analysis predicts Ile377Thr is damaging to the protein structure/function. However, only one disease-causing mutation in a nearby residue (Arg388Trp) has been reported (Watkins D et al., 2009), indicating this region of the protein may tolerate change. With the clinical and molecular information available at this time, we cannot definitively determine if Ile377Thr in the PKP2 gene is a disease-causing mutation or a rare benign variant. The variant is found in ARVC panel(s).
Invitae RCV000640003 SCV000761590 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2017-12-11 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 377 of the PKP2 protein (p.Ile377Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs397516985, ExAC 0.01%). This variant has not been reported in the literature in individuals with PKP2-related disease. ClinVar contains an entry for this variant (Variation ID: 45009). 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. 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.