rs727504432
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001005242.3(PKP2):c.2377del(p.Ser793ValfsTer94) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S793S) has been classified as Likely benign.
Frequency
Consequence
NM_001005242.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKP2 | NM_001005242.3 | c.2377del | p.Ser793ValfsTer94 | frameshift_variant | 12/13 | ENST00000340811.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKP2 | ENST00000340811.9 | c.2377del | p.Ser793ValfsTer94 | frameshift_variant | 12/13 | 1 | NM_001005242.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461806Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727226
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular cardiomyopathy Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 21, 2017 | The p.Ser837fs variant in PKP2 has been reported in >10 individuals with clinica l features of ARVC (Gerull 2004, Dalal 2006, Dalal 2006, Dalal 2009, Xu 2010, An toniades 2006, Fressart 2009, Barahona-Dussault 2010, Den Haan 2009, Watkins 200 9, Tan, 2010, Cox 2011, Baskin 2013) and was absent from large population studie s. It has also been reported by other clinical laboratories in ClinVar (Variatio n ID 177995). This variant causes a frameshift, which is predicted to replace th e last 45 amino acid residues of the protein with 93 aberrant residues. This alt eration is predicted to lead to an elongated protein with a termination codon th at is 94 amino acids downstream of the frameshift. In summary, although addition al functional studies are required to fully establish its clinical significance, the p.Ser837fs variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PS 4_M, PM4 (Richards 2015). - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | May 07, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 19, 2023 | This variant deletes 1 nucleotide in exon 13 of the PKP2 gene, creating a frameshift in the last exon. This mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing altered C-terminal sequence. To our knowledge, functional studies have not been reported for this variant. This variant has been reported to segregate with arrhythmogenic right ventricular cardiomyopathy in multiple families (PMID: 16893920, 17010805). This variant has been reported in over 10 unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 15489853, 16549640, 19880068, 20031617, 20152563, 21606396, 23871674, 24585727 ). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Arrhythmogenic right ventricular dysplasia 9 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Heidelberg University | Mar 08, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change results in a frameshift in the PKP2 gene (p.Ser837Valfs*94). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 45 amino acid(s) of the PKP2 protein and extend the protein by 48 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 15489853, 16549640, 16893920, 17010805, 19880068, 20031617, 20152563, 21606396, 23871674, 24585727). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 177995). For these reasons, this variant has been classified as Pathogenic. - |
Cardiomyopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 18, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 17, 2022 | This variant deletes 1 nucleotide in exon 13 of the PKP2 gene, creating a frameshift in the last exon. This mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing altered C-terminal sequence. This variant has been reported in over 10 unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 15489853, 16549640, 19880068, 20031617, 20152563, 21606396, 23871674, 24585727) and has been shown to segregate with disease in multiple families (PMID: 16893920, 17010805). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 10, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation, as the last 45 amino acids are replaced with 93 different amino acids, and other frameshift and missense variants within the residues lost have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 23812740, 15489853, 19863551, 29997227, 29606362, 17010805, 24585727, 23871674, 21606396, 19880068, 18382419, 19358943, 20857253, 20031617, 16893920, 27532257, 30790397, 30764827, 31447099, 32372669, 31402444, 32522011, 25825460, 31386562, 34120153, 35819174, 36139162, 31319917, 16549640, 20400443, VouliotisA2015[CaseReport], 19279339, 20152563) - |
Ventricular tachycardia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Sep 15, 2018 | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 09, 2024 | The c.2509delA pathogenic mutation, located in coding exon 13 of the PKP2 gene, results from a deletion of one nucleotide at position 2509, causing a translational frameshift with a predicted alternate stop codon (p.S837Vfs*94). This alteration occurs at the 3' terminus of thePKP2 gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 48 amino acids. This frameshift impacts the last 45amino acids of the native protein. However, frameshifts are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant has been reported in multiple unrelated individuals with confirmed or suspected arrhythmogenic right ventricular cardiomyopathy (ARVC) (Gerull B et al. Nat Genet. 2004;36(11):1162-4; Dalal D et al. Circulation. 2006;113(13):1641-9; Dalal D et al. J Am Coll Cardiol. 2006;48(7):1416-24; Watkins DA et al. Heart Rhythm. 2009;6(11 Suppl):S10-7; Fressart V et al. Europace. 2010;12(6):861-8; Cox MG et al. Circulation. 2011;123(23):2690-700; Baskin B et al. Hum Genet. 2013;132(11):1245-52; Philips B et al. Circ Arrhythm Electrophysiol. 2014;7(2):230-6; Hermida A. Eur. J. Heart Fail. 2019;21(6):792-800). This variant was also reported to co-segregate with disease in a few small families with ARVC (Antoniades L et al. Eur Heart J. 2006;27(18):2208-16; Vouliotis A et al. Hosp Chron. 2015;10(3):166-173; Xu T. J. Am. Coll. Cardiol. 2010;55(6):587-97). This variant was also detected in an eight year old proband with hypertrophic cardiomyopathy and her unaffected father (Haggerty CM. Circ Genom Precis Med. 2018 Jul;11(7):e002237). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Familial isolated arrhythmogenic right ventricular dysplasia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 14, 2022 | Variant summary: PKP2 c.2509delA (p.Ser837ValfsX94) causes a frameshift which results in an extension of the protein. The variant was absent in 251916 control chromosomes. c.2509delA has been reported in the literature in multiple individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (example, Gerull_2004, Dalal_2006, den Haan_2009, Dalal_2006, Antoniades_2006, Asimaki_2009). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at