rs144601090
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP3_ModeratePP5BS2
The NM_001005242.3(PKP2):āc.1930T>Cā(p.Ser644Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,614,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S644F) has been classified as Uncertain significance.
Frequency
Consequence
NM_001005242.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKP2 | NM_001005242.3 | c.1930T>C | p.Ser644Pro | missense_variant | 9/13 | ENST00000340811.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKP2 | ENST00000340811.9 | c.1930T>C | p.Ser644Pro | missense_variant | 9/13 | 1 | NM_001005242.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000112 AC: 17AN: 152132Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251382Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135860
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461860Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17AN XY: 727234
GnomAD4 genome ? AF: 0.000112 AC: 17AN: 152250Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74434
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular cardiomyopathy Pathogenic:1Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 06, 2021 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Jun 28, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Nov 24, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | 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. - |
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Arrhythmogenic right ventricular dysplasia 9 Pathogenic:1Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 15, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | May 31, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not provided Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 26, 2021 | 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) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 30, 2022 | PP3 - |
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Sep 13, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 05, 2023 | 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. - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 27, 2024 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at