Submissions for variant NM_001005242.3(PKP2):c.964G>A (p.Gly322Ser)

dbSNP: rs200069860

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497362	SCV000590164	uncertain significance	not provided	2019-05-17	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV001237125	SCV001409876	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2022-02-20	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 322 of the PKP2 protein (p.Gly322Ser). This variant is present in population databases (rs200069860, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PKP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 432440). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001237125	SCV002557099	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with arrhythmogenic right ventricular dysplasia 9 (ARVD9; MIM#609040). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 17010805, 23183494). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 17010805, 23183494). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2 & v3) <0.001 for a dominant condition (10 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2 & v3) (50 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0708 - Another missense variant comparable to the one identified in this case has conflicting previous evidence for pathogenicity. p.(Gly322Cys) has been regarded as both likely benign and VUS in ClinVar. In addition, it was found that carriers had a lower average left ventricular mass than noncarriers (PMID: 29288195) and it was detected in an individual with HCM and classified as a VUS (PMID: 30847666). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported as VUS in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Color Diagnostics, LLC DBA Color Health	RCV003532147	SCV004358907	uncertain significance	Cardiomyopathy	2023-11-27	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 322 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 been identified in 9/281928 chromosomes 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.
All of Us Research Program, National Institutes of Health	RCV004003502	SCV004846453	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 322 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 cardiovascular disorders in the literature. This variant has been identified in 9/281928 chromosomes 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000497362	SCV001554067	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PKP2 p.Gly322Ser variant was not identified in the literature but was identified in dbSNP (ID: rs200069860) and ClinVar (classified as uncertain significance by GeneDx). The variant was identified in control databases in 9 of 281928 chromosomes at a frequency of 0.00003192 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: East Asian in 7 of 19946 chromosomes (freq: 0.000351), Latino in 1 of 35426 chromosomes (freq: 0.000028) and European (non-Finnish) in 1 of 128342 chromosomes (freq: 0.000008), but was not observed in the African, Ashkenazi Jewish, European (Finnish), Other, or South Asian populations. The p.Gly322 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.