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

gnomAD frequency: 0.00001  dbSNP: rs397516985

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	2021-09-21	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 but additional evidence is not available (ClinVar Variant ID# 45009; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Labcorp Genetics (formerly Invitae), Labcorp	RCV000640003	SCV000761590	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2017-12-04	criteria provided, single submitter	clinical testing	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. 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 has not been reported in the literature in individuals with PKP2-related disease. ClinVar contains an entry for this variant (Variation ID: 45009). This variant is present in population databases (rs397516985, ExAC 0.01%). 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.
Duke University Health System Sequencing Clinic, Duke University Health System	RCV000640003	SCV003918987	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2023-04-20	criteria provided, single submitter	research
Ambry Genetics	RCV004018864	SCV005004300	uncertain significance	Cardiovascular phenotype	2020-04-22	criteria provided, single submitter	clinical testing	The c.1130T>C (p.I377T) alteration is located in exon 4 (coding exon 4) of the PKP2 gene. This alteration results from a T to C substitution at nucleotide position 1130, causing the isoleucine (I) at amino acid position 377 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.