Submissions for variant NM_001005242.3(PKP2):c.1379-2072C>T

gnomAD frequency: 0.00005  dbSNP: rs758950276

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000477349	SCV000545230	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 472 of the PKP2 protein (p.Pro472Leu). This variant is present in population databases (rs758950276, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 36178741). ClinVar contains an entry for this variant (Variation ID: 406546). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825814	SCV000967284	likely benign	not specified	2018-03-22	criteria provided, single submitter	clinical testing	p.Pro472Leu in exon6 of PKP2: This variant is classified as likely benign due to a lack of conservation across species, including mammals. Of note, 7 mammals (o rangutan, gibbon, macaque, baboon, green monkey, marmoset, squirrel monkey) have a Leu at this position despite high nearby amino acid conservation. In addition , computational prediction tools do not suggest a high likelihood of impact to t he protein. ACMG/AMP Criteria applied: BP4_Strong.
Color Diagnostics, LLC DBA Color Health	RCV001182494	SCV001347958	likely benign	Cardiomyopathy	2018-11-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002393098	SCV002702961	likely benign	Cardiovascular phenotype	2018-11-28	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000825814	SCV003844356	uncertain significance	not specified	2023-02-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003392275	SCV004119896	uncertain significance	PKP2-related disorder	2022-11-23	criteria provided, single submitter	clinical testing	The PKP2 c.1415C>T variant is predicted to result in the amino acid substitution p.Pro472Leu. To our knowledge, this variant has not been reported in the literature. Of note, in multiple species a leucine (Leu) is present at the Pro472 residue. This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-32996211-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.