Submissions for variant NM_001005242.3(PKP2):c.173A>G (p.Glu58Gly)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002399302	SCV002710234	uncertain significance	Cardiovascular phenotype	2022-07-11	criteria provided, single submitter	clinical testing	The p.E58G variant (also known as c.173A>G), located in coding exon 1 of the PKP2 gene, results from an A to G substitution at nucleotide position 173. The glutamic acid at codon 58 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003507445	SCV004318386	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2023-09-29	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. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 1779151). This variant has not been reported in the literature in individuals affected with PKP2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 58 of the PKP2 protein (p.Glu58Gly).
All of Us Research Program, National Institutes of Health	RCV004007358	SCV004829224	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2023-10-23	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 58 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 PKP2-related disorders in the literature. This variant has not been identified 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	RCV004763405	SCV005372743	uncertain significance	not provided	2023-07-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge