Submissions for variant NM_001005242.3(PKP2):c.464G>C (p.Ser155Thr)

gnomAD frequency: 0.00004  dbSNP: rs141438322

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172092	SCV000054798	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038220	SCV000061888	uncertain significance	not specified	2015-04-29	criteria provided, single submitter	clinical testing	The p.Ser155Thr variant in PKP2 has been identified by our laboratory in 1 Cauca sian adult with HCM, who carried a possibly disease-causing variant in another g ene. It has also been identified in 2/66652 European chromosomes and 2/11576 Lat ino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinst itute.org; dbSNP rs141438322). Computational prediction tools and evolutionary c onservation analyses suggest that this variant may not impact the protein, thoug h this information is not predictive enough to rule out pathogenicity. In summar y, the clinical significance of the p.Ser155Thr variant is uncertain.
Ambry Genetics	RCV000245887	SCV000319582	uncertain significance	Cardiovascular phenotype	2022-08-15	criteria provided, single submitter	clinical testing	The c.464G>C (p.S155T) alteration is located in exon 3 (coding exon 3) of the PKP2 gene. This alteration results from a G to C substitution at nucleotide position 464, causing the serine (S) at amino acid position 155 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000537190	SCV000638903	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 155 of the PKP2 protein (p.Ser155Thr). This variant is present in population databases (rs141438322, gnomAD 0.009%). 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: 45079). 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 disruptive. 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.
Color Diagnostics, LLC DBA Color Health	RCV000771889	SCV000904651	uncertain significance	Cardiomyopathy	2022-11-28	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 155 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 cardiovascular disorders in the literature. This variant has been identified in 15/282824 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845440	SCV000987515	uncertain significance	Primary familial dilated cardiomyopathy		criteria provided, single submitter	clinical testing
Genetics and Genomics Program, Sidra Medicine	RCV001293165	SCV001434162	uncertain significance	Primary dilated cardiomyopathy		criteria provided, single submitter	research
GeneDx	RCV000172092	SCV001789041	likely benign	not provided	2020-12-10	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23861362)
Revvity Omics, Revvity	RCV000537190	SCV003808500	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2021-12-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996386	SCV004846527	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 155 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 cardiovascular disorders in the literature. This variant has been identified in 15/282824 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000172092	SCV001928944	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172092	SCV001974408	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000172092	SCV001978606	uncertain significance	not provided		no assertion criteria provided	clinical testing