ClinVar Miner

Submissions for variant NM_004572.3(PKP2):c.746G>A (p.Ser249Asn) (rs1085307949)

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 RCV000489016 SCV000577719 uncertain significance not provided 2017-06-26 criteria provided, single submitter clinical testing The S249N variant in the PKP2 gene has been reported in one individual, who also harbored a deletion of exon 8 in the PKP2 gene, from a ARVC registry cohort (Bhonsale et al., 2015). Not all individuals in this cohort were diagnosed with definite ARVC, and specific clinical details about this proband were not provided. The S249N variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species, and the majority (2 out of 3) of in silico analyses predict this variant is probably damaging to the protein structure/function. Nevertheless, the S249N variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. A missense variant at the same residue (S249T) has been reported in the Human Gene Mutation Database in association with ARVC (Stenson et al., 2014), though the precise clinical significance of this variant has not been determined.
Invitae RCV000640012 SCV000761599 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 249 of the PKP2 protein (p.Ser249Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with arrythmogenic right ventricular cardiomyopathy (ARVC) who also carried a PKP2 pathogenic variant (PMID: 25616645). ClinVar contains an entry for this variant (Variation ID: 427088). 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.