Submissions for variant NM_001005242.3(PKP2):c.826C>T (p.Pro276Ser)

gnomAD frequency: 0.00010  dbSNP: rs201944276

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172583	SCV000051040	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154802	SCV000204482	uncertain significance	not specified	2014-08-08	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Pro276Ser varia nt in PKP2 has not been reported in individuals with cardiomyopathy but was iden tified in 1/1093 chromosomes by the ClinSeq project and in 2/8600 European Ameri can chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington. edu/EVS/; dbSNP rs201944276). Proline (Pro) at position 276 is not conserved in mammals and evolutionarily distant species and the change to Serine (Ser) is pre sent in 6 mammals including hamster, bushbaby, dolphin, killer whale, tenrec and tasmanian devil; however, the local alignment of this region is poor. Additiona l computational prediction tools indicate this variant may not impact the protei n, though this information is not predictive enough to rule out pathogenicity. I n summary, while the clinical significance of the Pro276Ser variant is uncertain , conservation data suggest that it is more likely to be benign.
GeneDx	RCV000154802	SCV000236178	likely benign	not specified	2016-03-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000244304	SCV000318036	likely benign	Cardiovascular phenotype	2017-06-12	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV001081729	SCV000761617	likely benign	Arrhythmogenic right ventricular dysplasia 9	2023-12-31	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852678	SCV000995386	likely benign	Cardiomyopathy	2018-05-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001081729	SCV001269900	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health	RCV000852678	SCV001356680	likely benign	Cardiomyopathy	2018-11-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000172583	SCV002545022	likely benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing	PKP2: BP4