Reported in association with ARVC and sudden unexplained death, however, specific clinical information or segregation data were not provided (van Tintelen et al., 2006; Cox et al., 2011; Kapplinger et al., 2011; Quarta et al., 2011; Zhang et al., 2012; Shanks et al., 2018); 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 (Belkaya et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar (ClinVar Variant ID# 45055; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 21606396, 31386562, 21636032, 24033266, 22019812, 21606390, 16567567, 27532257, 20031616, 25637381, 23299917, 28359509, 29915097, 23871674, 31402444, 32522011, 33232181)
ClinVar Genomic variation as it relates to human health
NM_001005242.3(PKP2):c.1930T>C (p.Ser644Pro)
Germline
Classification
Help
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.
(15)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Conflicting classifications of pathogenicity
Likely pathogenic(3); Uncertain significance(10)
Likely pathogenic(3); Uncertain significance(10)
15
criteria provided, conflicting classifications
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: VCV000045055.37
- 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 Aug 11, 2024 Mar 27, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_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 - Protein change
- S688P, S644P
- Other names
- -
- Canonical SPDI
- NC_000012.12:32821438:A:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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
The Genome Aggregation Database (gnomAD) 0.00011
Trans-Omics for Precision Medicine (TOPMed) 0.00012
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
1943 | 1996 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Dec 13, 2023 | RCV000038195.10 | |
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Jan 29, 2024 | RCV000468300.17 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Mar 27, 2024 | RCV000618784.5 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Jun 30, 2022 | RCV000766576.4 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
May 5, 2023 | RCV001171161.7 |
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. |
More information
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
(Jan 26, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000236246.9
First in ClinVar: Jul 05, 2015 Last updated: Apr 17, 2019 |
Comment:
Reported in association with ARVC and sudden unexplained death, however, specific clinical information or segregation data were not provided (van Tintelen et al., 2006; Cox … (more)
Reported in association with ARVC and sudden unexplained death, however, specific clinical information or segregation data were not provided (van Tintelen et al., 2006; Cox et al., 2011; Kapplinger et al., 2011; Quarta et al., 2011; Zhang et al., 2012; Shanks et al., 2018); 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 (Belkaya et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar (ClinVar Variant ID# 45055; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 21606396, 31386562, 21636032, 24033266, 22019812, 21606390, 16567567, 27532257, 20031616, 25637381, 23299917, 28359509, 29915097, 23871674, 31402444, 32522011, 33232181) (less)
|
|
|
Uncertain significance
(Jun 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226319.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular dysplasia 9
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000545229.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
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). … (more)
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; Invitae). 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)
|
|
|
Uncertain Significance
(Oct 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061862.8
First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024 |
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 … (more)
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)
|
|
|
Likely pathogenic
(Nov 24, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular cardiomyopathy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000264145.2
First in ClinVar: Jan 31, 2015 Last updated: Jan 31, 2015 |
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(May 31, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular dysplasia 9
Affected status: yes
Allele origin:
germline
|
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 |
|
|
|
Uncertain significance
(Jun 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial isolated arrhythmogenic right ventricular dysplasia
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000747967.1
First in ClinVar: Jan 31, 2015 Last updated: Jan 31, 2015 |
|
|
|
Uncertain significance
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular dysplasia 9
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001138678.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Uncertain significance
(Sep 13, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001333846.2
First in ClinVar: May 31, 2020 Last updated: Mar 11, 2023 |
|
|
|
Uncertain significance
(Jul 15, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular dysplasia 9
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003808497.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Uncertain significance
(May 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001356775.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
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 … (more)
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). 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)
|
|
|
Uncertain Significance
(Dec 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004845951.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 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)
|
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 … (more)
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). 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)
Number of individuals with the variant: 12
|
|
|
Likely pathogenic
(Mar 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000737842.7
First in ClinVar: Apr 14, 2018 Last updated: Aug 11, 2024 |
Comment:
The p.S688P variant (also known as c.2062T>C), located in coding exon 10 of the PKP2 gene, results from a T to C substitution at nucleotide … (more)
The p.S688P variant (also known as c.2062T>C), located in coding exon 10 of the PKP2 gene, results from a T to C substitution at nucleotide position 2062. The serine at codon 688 is replaced by proline, an amino acid with similar properties. This variant has been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) (van Tintelen JP et al. Circulation, 2006 Apr;113:1650-8; Quarta G et al. Circulation, 2011 Jun;123:2701-9; Zhang M et al. Circ. J., 2012 Oct;76:189-94; DeWitt ES et al. J Am Coll Cardiol, 2019 07;74:346-358; Goudal A et al. Hum Mutat, 2022 Sep;43:1333-1342; Olivetti NQS et al. Circ Arrhythm Electrophysiol, 2023 Feb;16:e011391). This variant has also been seen in sudden death and exome cohorts, but cardiovascular details were limited or not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28; Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Shanks GW et al. Circulation, 2018 06;137:2705-2715). Based on internal structural analysis, this variant is highly destabilizing to the local structure (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
|
|
|
Uncertain significance
(Jun 01, 2014)
|
no assertion criteria provided
Method: research
|
Arrhythmogenic right ventricular dysplasia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
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
|
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001924771.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
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; Invitae). 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 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 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). 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:
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). 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:
The p.S688P variant (also known as c.2062T>C), located in coding exon 10 of the PKP2 gene, results from a T to C substitution at nucleotide position 2062. The serine at codon 688 is replaced by proline, an amino acid with similar properties. This variant has been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) (van Tintelen JP et al. Circulation, 2006 Apr;113:1650-8; Quarta G et al. Circulation, 2011 Jun;123:2701-9; Zhang M et al. Circ. J., 2012 Oct;76:189-94; DeWitt ES et al. J Am Coll Cardiol, 2019 07;74:346-358; Goudal A et al. Hum Mutat, 2022 Sep;43:1333-1342; Olivetti NQS et al. Circ Arrhythm Electrophysiol, 2023 Feb;16:e011391). This variant has also been seen in sudden death and exome cohorts, but cardiovascular details were limited or not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28; Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Shanks GW et al. Circulation, 2018 06;137:2705-2715). Based on internal structural analysis, this variant is highly destabilizing to the local structure (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Reported in association with ARVC and sudden unexplained death, however, specific clinical information or segregation data were not provided (van Tintelen et al., 2006; Cox et al., 2011; Kapplinger et al., 2011; Quarta et al., 2011; Zhang et al., 2012; Shanks et al., 2018); 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 (Belkaya et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar (ClinVar Variant ID# 45055; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 21606396, 31386562, 21636032, 24033266, 22019812, 21606390, 16567567, 27532257, 20031616, 25637381, 23299917, 28359509, 29915097, 23871674, 31402444, 32522011, 33232181)
Comment:
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; Invitae). 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 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 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). 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:
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). 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:
The p.S688P variant (also known as c.2062T>C), located in coding exon 10 of the PKP2 gene, results from a T to C substitution at nucleotide position 2062. The serine at codon 688 is replaced by proline, an amino acid with similar properties. This variant has been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) (van Tintelen JP et al. Circulation, 2006 Apr;113:1650-8; Quarta G et al. Circulation, 2011 Jun;123:2701-9; Zhang M et al. Circ. J., 2012 Oct;76:189-94; DeWitt ES et al. J Am Coll Cardiol, 2019 07;74:346-358; Goudal A et al. Hum Mutat, 2022 Sep;43:1333-1342; Olivetti NQS et al. Circ Arrhythm Electrophysiol, 2023 Feb;16:e011391). This variant has also been seen in sudden death and exome cohorts, but cardiovascular details were limited or not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28; Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Shanks GW et al. Circulation, 2018 06;137:2705-2715). Based on internal structural analysis, this variant is highly destabilizing to the local structure (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 ...
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Record last updated Nov 10, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.