VCV000045055.46 - ClinVar

NM_001005242.3(PKP2):c.1930T>C (p.Ser644Pro)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Likely pathogenic (2); Uncertain significance (11)

13 out of 15 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001005242.3(PKP2):c.1930T>C (p.Ser644Pro)

Variation ID: 45055 Accession: VCV000045055.46

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12p11.21 12: 32821439 (GRCh38) [ NCBI UCSC ] 12: 32974373 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 6, 2014	Jul 19, 2026	Apr 20, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_001005242.3:c.1930T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001005242.2:p.Ser644Pro	missense
NM_004572.4:c.2062T>C	NP_004563.2:p.Ser688Pro	missense
NC_000012.12:g.32821439A>G
NC_000012.11:g.32974373A>G
NG_009000.1:g.80408T>C
LRG_398:g.80408T>C
LRG_398t1:c.2062T>C	LRG_398p1:p.Ser688Pro

... more HGVS ... less HGVS

Protein change

S688P, S644P

Other names

Canonical SPDI

NC_000012.12:32821438:A:G

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (G)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00002

Exome Aggregation Consortium (ExAC) 0.00003

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

1000 Genomes Project 0.00020

1000 Genomes Project 30x 0.00016

The Genome Aggregation Database (gnomAD) 0.00011

Trans-Omics for Precision Medicine (TOPMed) 0.00012

Links

ClinGen: CA010659 dbSNP: rs144601090 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PKP2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2372	2432

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Arrhythmogenic right ventricular cardiomyopathy	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	Aug 6, 2024	RCV000038195.13
Arrhythmogenic right ventricular dysplasia 9	Conflicting classifications of pathogenicity (5)	criteria provided, conflicting classifications	Jan 26, 2026	RCV000468300.21
Cardiovascular phenotype	Likely pathogenic (1)	criteria provided, single submitter	Apr 20, 2026	RCV000618784.8
not provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Jan 28, 2025	RCV000766576.5
Cardiomyopathy	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	May 29, 2024	RCV001171161.8

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain Significance (Aug 06, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Arrhythmogenic right ventricular cardiomyopathy (Autosomal dominant inheritance)	All of Us Research Program, National Institutes of Health Accession: SCV004845951.2 First in ClinVar: Apr 20, 2024 Last updated: Dec 14, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (13) PubMed: 16567567‚ 20031616‚ 21606390‚ 21606396‚ 22019812‚ 25820315‚ 27532257‚ 28359509‚ 29915097‚ 31319917‚ 32522011‚ 36720007‚ 37418234 Comment: show This missense variant replaces serine with proline at codon 688 of the PKP2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with or suspected of arrhythmogenic right ventricular cardiomyopathy (PMID: 16567567, 20031616, 21606390, 21606396, 22019812, 25820315, 27532257, 31319917, 32522011, 36720007, 37418234). This variant has also been reported in an individual affected with acute myocarditis (PMID: 28359509) and in a young individual with sudden unexplained death (PMID: 29915097). This variant has also been identified in 11/282770 chromosomes (11/24964 African 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 15 Zygosity: 15 Single Heterozygotes

Uncertain significance (Jan 28, 2025) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000236246.10 First in ClinVar: Jul 05, 2015 Last updated: Feb 16, 2025	Comment: show Reported in a child with acute myocarditis who was compound heterozygous for a paternally inherited S688P variant and a maternally inherited D829N variant; all family members were reported as unaffected (PMID: 28359509); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21606396, 31386562, 24033266, 22019812, 21606390, 16567567, 27532257, 20031616, 25637381, 23299917, 29915097, 23871674, 31402444, 36175056, 32522011, 33232181, 35819174, 28359509, 21636032) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (Feb 09, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ISL SNV Classification Criteria 03 February 2026)	Arrhythmogenic right ventricular dysplasia 9	Illumina Laboratory Services, Illumina Accession: SCV007449719.1 First in ClinVar: Feb 15, 2026 Last updated: Feb 15, 2026	Publications: PubMed (15) PubMed: 16567567‚ 20031616‚ 21606390‚ 21606396‚ 21636032‚ 22019812‚ 25820315‚ 27532257‚ 28359509‚ 29915097‚ 31319917‚ 31386562‚ 32522011‚ 35819174‚ 36175056 Comment: show The PKP2 c.1930T>C p.(Ser644Pro) missense variant, which is also referred to as c.2062T>C p.(Ser688Pro), has been reported in at least 13 unrelated individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 16567567; 20031616; 21606390; 21606396; 21636032; 22019812; 25820315; 27532257; 31386562; 31319917; 32522011; 35819174). It has also been reported in association with sudden unexplained death in the young and myocarditis (PMID: 29915097; 28359509; 36175056). The highest frequency of this allele in the Genome Aggregation Database is 0.000441 in the African/African American population (version 2.1.1). This frequency is high but may be consistent with reduced penetrance. Missense variants in this gene are not the typical mechanism of disease, but multiple lines of computational evidence suggest the variant may impact the gene or gene product. Based on the available evidence, the c.1930T>C p.(Ser644Pro) variant is classified as a variant of uncertain significance for arrhythmogenic right ventricular cardiomyopathy. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Uncertain significance (May 31, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ACGS Guidelines, 2013)	Arrhythmogenic right ventricular dysplasia 9	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV000744697.1 First in ClinVar: Apr 17, 2017 Last updated: Apr 17, 2017	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (May 28, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Arrhythmogenic right ventricular dysplasia 9	Mendelics Accession: SCV001138678.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Uncertain significance (Sep 13, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV001333846.2 First in ClinVar: May 31, 2020 Last updated: Mar 11, 2023	Publications: PubMed (1) PubMed: 25741868 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Jun 30, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004226319.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (13) PubMed: 16567567‚ 20031616‚ 21606390‚ 22019812‚ 27532257‚ 28359509‚ 29915097‚ 31319917‚ 31386562‚ 31402444‚ 32522011‚ 33232181‚ 34120153 Comment: show PP3 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 1

Uncertain Significance (Oct 06, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Arrhythmogenic right ventricular cardiomyopathy	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000061862.8 First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024	Publications: PubMed (12) PubMed: 16567567‚ 20031616‚ 21606390‚ 21606396‚ 21636032‚ 22019812‚ 23299917‚ 27532257‚ 28359509‚ 29915097‚ 31319917‚ 31386562 Comment: show The p.Ser688Pro variant in PKP2 has been reported in 5 individuals with ARVC (van Tintelen 2006 PMID: 16567567, Quarta 2011 PMID: 21606390, and Zhang 2012 PMID: 22019812, Walsh 2017 PMID: 27532257, DeWitt 2019 PMID: 31319917, van Lint 2019 PMID: 31386562), in 1 individual with sudden unexplained death in the young (SUDY) (Shanks 2018 PMID: 29915097) and identified by our laboratory in 1 individual with DCM and ARVC and 2 individuals with ARVC. It has also been identified in 0.044% (11/24964) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Moderate, PP3. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Jul 15, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Arrhythmogenic right ventricular dysplasia 9	Revvity Omics, Revvity Accession: SCV003808497.3 First in ClinVar: Mar 04, 2023 Last updated: Sep 06, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Jan 26, 2026) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Arrhythmogenic right ventricular dysplasia 9	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000545229.12 First in ClinVar: Apr 17, 2017 Last updated: Feb 15, 2026	Publications: PubMed (8) PubMed: 16567567‚ 21606390‚ 22019812‚ 27532257‚ 28492532‚ 31319917‚ 32522011‚ 36720007 Comment: show This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 688 of the PKP2 protein (p.Ser688Pro). This variant is present in population databases (rs144601090, gnomAD 0.05%). This missense change has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 16567567, 21606390, 22019812, 27532257, 31319917, 32522011, 36720007; internal data). ClinVar contains an entry for this variant (Variation ID: 45055). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Apr 20, 2026) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV000737842.10 First in ClinVar: Apr 14, 2018 Last updated: Jul 19, 2026	Publications: PubMed (9) PubMed: 16567567‚ 21606390‚ 22019812‚ 23299917‚ 25637381‚ 29915097‚ 31319917‚ 35819174‚ 36720007 Comment: show The c.2062T>C (p.S688P) alteration is located in exon 10 (coding exon 10) of the PKP2 gene. This alteration results from a T to C substitution at nucleotide position 2062, causing the serine (S) at amino acid position 688 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of 0.004% (11/282770) total alleles studied. The highest observed frequency was 0.044% (11/24964) of African alleles. This variant has been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) (van Tintelen, 2006; Quarta, 2011; Zhang, 2012; DeWitt, 2019; Goudal, 2022; Olivetti, 2023). This variant has also been seen in sudden death and exome cohorts, but cardiovascular details were limited or not provided (Andreasen, 2013; Amendola, 2015; Shanks, 2018). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this variant is highly destabilizing to the local structure (Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Jun 28, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Familial isolated arrhythmogenic right ventricular dysplasia	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV000747967.1 First in ClinVar: Jan 31, 2015 Last updated: Jan 31, 2015	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (May 29, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	Color Diagnostics, LLC DBA Color Health Accession: SCV001356775.4 First in ClinVar: Jun 22, 2020 Last updated: May 03, 2025	Publications: PubMed (13) PubMed: 16567567‚ 20031616‚ 21606390‚ 21606396‚ 22019812‚ 25820315‚ 27532257‚ 28359509‚ 29915097‚ 31319917‚ 32522011‚ 36720007‚ 37418234 Comment: show This missense variant replaces serine with proline at codon 688 of the PKP2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with or suspected of arrhythmogenic right ventricular cardiomyopathy (PMID: 16567567, 20031616, 21606390, 21606396, 22019812, 25820315, 27532257, 31319917, 32522011, 36720007, 37418234). This variant has also been reported in an individual affected with acute myocarditis (PMID: 28359509) and in a young individual with sudden unexplained death (PMID: 29915097). This variant has also been identified in 11/282770 chromosomes (11/24964 African 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Platform type: NGS

Uncertain significance (Jun 01, 2014) N Not contributing to aggregate classification	no assertion criteria provided	Arrhythmogenic right ventricular dysplasia (Autosomal dominant inheritance)	CSER _CC_NCGL, University of Washington Study: ESP 6500 variant annotation Accession: SCV000190465.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014 Comment: Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript	Observation: 1 Collection method: research Allele origin: germline Affected status: unknown Observation 1 Collection method: research Allele origin: germline Affected status: unknown

Uncertain significance (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Clinical Genetics, Academic Medical Center Study: VKGL Data-share Consensus Accession: SCV001924771.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Comment:

This missense variant replaces serine with proline at codon 688 of the PKP2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with or suspected of arrhythmogenic right ventricular cardiomyopathy (PMID: 16567567, 20031616, 21606390, 21606396, 22019812, 25820315, 27532257, 31319917, 32522011, 36720007, 37418234). This variant has also been reported in an individual affected with acute myocarditis (PMID: 28359509) and in a young individual with sudden unexplained death (PMID: 29915097). This variant has also been identified in 11/282770 chromosomes (11/24964 African 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.

Comment:

Reported in a child with acute myocarditis who was compound heterozygous for a paternally inherited S688P variant and a maternally inherited D829N variant; all family members were reported as unaffected (PMID: 28359509); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21606396, 31386562, 24033266, 22019812, 21606390, 16567567, 27532257, 20031616, 25637381, 23299917, 29915097, 23871674, 31402444, 36175056, 32522011, 33232181, 35819174, 28359509, 21636032)

Comment:

The PKP2 c.1930T>C p.(Ser644Pro) missense variant, which is also referred to as c.2062T>C p.(Ser688Pro), has been reported in at least 13 unrelated individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 16567567; 20031616; 21606390; 21606396; 21636032; 22019812; 25820315; 27532257; 31386562; 31319917; 32522011; 35819174). It has also been reported in association with sudden unexplained death in the young and myocarditis (PMID: 29915097; 28359509; 36175056). The highest frequency of this allele in the Genome Aggregation Database is 0.000441 in the African/African American population (version 2.1.1). This frequency is high but may be consistent with reduced penetrance. Missense variants in this gene are not the typical mechanism of disease, but multiple lines of computational evidence suggest the variant may impact the gene or gene product. Based on the available evidence, the c.1930T>C p.(Ser644Pro) variant is classified as a variant of uncertain significance for arrhythmogenic right ventricular cardiomyopathy.

Comment:

The p.Ser688Pro variant in PKP2 has been reported in 5 individuals with ARVC (van Tintelen 2006 PMID: 16567567, Quarta 2011 PMID: 21606390, and Zhang 2012 PMID: 22019812, Walsh 2017 PMID: 27532257, DeWitt 2019 PMID: 31319917, van Lint 2019 PMID: 31386562), in 1 individual with sudden unexplained death in the young (SUDY) (Shanks 2018 PMID: 29915097) and identified by our laboratory in 1 individual with DCM and ARVC and 2 individuals with ARVC. It has also been identified in 0.044% (11/24964) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Moderate, PP3.

Comment:

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 688 of the PKP2 protein (p.Ser688Pro). This variant is present in population databases (rs144601090, gnomAD 0.05%). This missense change has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 16567567, 21606390, 22019812, 27532257, 31319917, 32522011, 36720007; internal data). ClinVar contains an entry for this variant (Variation ID: 45055). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Comment:

The c.2062T>C (p.S688P) alteration is located in exon 10 (coding exon 10) of the PKP2 gene. This alteration results from a T to C substitution at nucleotide position 2062, causing the serine (S) at amino acid position 688 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of 0.004% (11/282770) total alleles studied. The highest observed frequency was 0.044% (11/24964) of African alleles. This variant has been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) (van Tintelen, 2006; Quarta, 2011; Zhang, 2012; DeWitt, 2019; Goudal, 2022; Olivetti, 2023). This variant has also been seen in sudden death and exome cohorts, but cardiovascular details were limited or not provided (Andreasen, 2013; Amendola, 2015; Shanks, 2018). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this variant is highly destabilizing to the local structure (Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A Systematic Analysis of the Clinical Outcome Associated with Multiple Reclassified Desmosomal Gene Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Patients.	Nagyova E	Journal of cardiovascular translational research	2023	PMID: 37418234
Clinical Features, Genetic Findings, and Risk Stratification in Arrhythmogenic Right Ventricular Cardiomyopathy: Data From a Brazilian Cohort.	Olivetti NQS	Circulation. Arrhythmia and electrophysiology	2023	PMID: 36720007
Acute Myocarditis Associated With Desmosomal Gene Variants.	Ammirati E	JACC. Heart failure	2022	PMID: 36175056
Burden of rare variants in arrhythmogenic cardiomyopathy with right dominant form-associated genes provides new insights for molecular diagnosis and clinical management.	Goudal A	Human mutation	2022	PMID: 35819174
The genetic architecture of Plakophilin 2 cardiomyopathy.	Dries AM	Genetics in medicine : official journal of the American College of Medical Genetics	2021	PMID: 34120153
Impact of Genetic Variant Reassessment on the Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy Based on the 2010 Task Force Criteria.	Costa S	Circulation. Genomic and precision medicine	2021	PMID: 33232181
Inherited Cardiomyopathies Revealed by Clinically Suspected Myocarditis: Highlights From Genetic Testing.	Ader F	Circulation. Genomic and precision medicine	2020	PMID: 32522011
Reevaluation of genetic variants previously associated with arrhythmogenic right ventricular cardiomyopathy integrating population-based cohorts and proteomics data.	Ye JZ	Clinical genetics	2019	PMID: 31402444
Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Desmosomal Variants Are Rarely De Novo.	van Lint FHM	Circulation. Genomic and precision medicine	2019	PMID: 31386562
Phenotypic Manifestations of Arrhythmogenic Cardiomyopathy in Children and Adolescents.	DeWitt ES	Journal of the American College of Cardiology	2019	PMID: 31319917
Importance of Variant Interpretation in Whole-Exome Molecular Autopsy: Population-Based Case Series.	Shanks GW	Circulation	2018	PMID: 29915097
Autosomal Recessive Cardiomyopathy Presenting as Acute Myocarditis.	Belkaya S	Journal of the American College of Cardiology	2017	PMID: 28359509
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.	Walsh R	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 27532257
Clinical Presentation, Long-Term Follow-Up, and Outcomes of 1001 Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Patients and Family Members.	Groeneweg JA	Circulation. Cardiovascular genetics	2015	PMID: 25820315
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
Actionable exomic incidental findings in 6503 participants: challenges of variant classification.	Amendola LM	Genome research	2015	PMID: 25637381
New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants.	Andreasen C	European journal of human genetics : EJHG	2013	PMID: 23299917
PKP2 mutations in sudden death from arrhythmogenic right ventricular cardiomyopathy (ARVC) and sudden unexpected death with negative autopsy (SUDNA).	Zhang M	Circulation journal : official journal of the Japanese Circulation Society	2012	PMID: 22019812
Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise.	Kapplinger JD	Journal of the American College of Cardiology	2011	PMID: 21636032
Arrhythmogenic right ventricular dysplasia/cardiomyopathy: pathogenic desmosome mutations in index-patients predict outcome of family screening: Dutch arrhythmogenic right ventricular dysplasia/cardiomyopathy genotype-phenotype follow-up study.	Cox MG	Circulation	2011	PMID: 21606396
Familial evaluation in arrhythmogenic right ventricular cardiomyopathy: impact of genetics and revised task force criteria.	Quarta G	Circulation	2011	PMID: 21606390
Desmoglein-2 and desmocollin-2 mutations in dutch arrhythmogenic right ventricular dysplasia/cardiomypathy patients: results from a multicenter study.	Bhuiyan ZA	Circulation. Cardiovascular genetics	2009	PMID: 20031616
Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy.	van Tintelen JP	Circulation	2006	PMID: 16567567
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Text-mined citations for rs144601090 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jul 27, 2026