The nonsense c.3764C>G, p.Ala1255Gly variant identified in the MYBPC3 gene has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 24125834, 27532257, 25765472). This variant is absent in gnomAD v3.1.1, suggesting it is not a common benign variant in the populations represented in this database. The variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNAdecay. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). Based on available evidence, this variant is classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001005242.3(PKP2):c.1063C>T (p.Arg355Ter)
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.
(6)
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.
Pathogenic/Likely pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001005242.3(PKP2):c.1063C>T (p.Arg355Ter)
Variation ID: 201977 Accession: VCV000201977.14
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p11.21 12: 32869034 (GRCh38) [ NCBI UCSC ] 12: 33021968 (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 May 29, 2016 Sep 16, 2024 Aug 10, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001005242.3:c.1063C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001005242.2:p.Arg355Ter nonsense NM_004572.4:c.1063C>T NP_004563.2:p.Arg355Ter nonsense NC_000012.12:g.32869034G>A NC_000012.11:g.33021968G>A NG_009000.1:g.32813C>T LRG_398:g.32813C>T LRG_398t1:c.1063C>T LRG_398p1:p.Arg355Ter - Protein change
- R355*
- Other names
- p.R355*:CGA>TGA
- Canonical SPDI
- NC_000012.12:32869033:G:A
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
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 |
1940 | 1993 | |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 10, 2024 | RCV000183731.4 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 8, 2024 | RCV001218972.9 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 28, 2023 | RCV003996831.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 1, 2023 | RCV004020235.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jul 16, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular dysplasia 9
Affected status: unknown
Allele origin:
inherited
|
New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV002548797.1 First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022 |
Comment:
The nonsense c.3764C>G, p.Ala1255Gly variant identified in the MYBPC3 gene has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 24125834, 27532257, 25765472). … (more)
The nonsense c.3764C>G, p.Ala1255Gly variant identified in the MYBPC3 gene has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 24125834, 27532257, 25765472). This variant is absent in gnomAD v3.1.1, suggesting it is not a common benign variant in the populations represented in this database. The variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNAdecay. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). Based on available evidence, this variant is classified as Pathogenic. (less)
Clinical Features:
Intellectual disability (present) , Self-injurious behavior (present)
Secondary finding: yes
|
|
|
Pathogenic
(Jan 08, 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: SCV001390884.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg355*) in the PKP2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg355*) in the PKP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). This variant is present in population databases (rs754912778, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 24125834, 25765472, 27532257). ClinVar contains an entry for this variant (Variation ID: 201977). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Nov 28, 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: SCV004839359.1
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 variant is predicted to result in loss of protein function through nonsense-mediated decay or protein truncation. Loss of function is an established mechanism of … (more)
This variant is predicted to result in loss of protein function through nonsense-mediated decay or protein truncation. Loss of function is an established mechanism of disease. It has been reported in multiple individuals with arrhythmogenic right ventricular cardiomyopathy or referred for cardiomyopathy genetic testing (PMID: 28491739, 25765472, 24125834, 27532257). This variant is rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). (less)
Number of individuals with the variant: 1
|
|
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Likely Pathogenic
(Mar 29, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Arrhythmogenic right ventricular cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848060.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Arg355X variant in PKP2 has been identified in 1 individual with ARVC (Bao 2013). This variant has also been identified in 1/8650 East Asian … (more)
The p.Arg355X variant in PKP2 has been identified in 1 individual with ARVC (Bao 2013). This variant has also been identified in 1/8650 East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs754912778) and has been reported in ClinVar (Variation ID: 201977). This nonsense variant leads to a premature termination codon at position 355, which is predicted to lead to a truncated or absent protein. Frameshift and other truncating variants in PKP2 are strongly associated with ARVC. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg355X variant is likely pathogenic. (less)
|
|
|
Pathogenic
(Dec 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV005022527.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The p.R355* pathogenic mutation (also known as c.1063C>T), located in coding exon 4 of the PKP2 gene, results from a C to T substitution at … (more)
The p.R355* pathogenic mutation (also known as c.1063C>T), located in coding exon 4 of the PKP2 gene, results from a C to T substitution at nucleotide position 1063. This changes the amino acid from an arginine to a stop codon within coding exon 4. This alteration has been reported in association with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Bao J et al. Circ Cardiovasc Genet, 2013 Dec;6:552-6; Zhou X et al. Eur J Med Genet, 2015 Apr;58:258-65; Castro SA et al. HeartRhythm Case Rep, 2016 Nov;2:469-472). This alteration has also been reported in biobank and whole exome sequencing cohorts (Haggerty CM et al. Genet Med, 2017 Nov;19:1245-1252; Xiao H et al. World J Pediatr, 2022 Oct;18:687-694; Bourfiss M et al. Circ Genom Precis Med, 2022 Dec;15:e003704). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Aug 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000236211.15
First in ClinVar: Jul 05, 2015 Last updated: Sep 16, 2024 |
Comment:
Identified in patients with ARVC in published literature (PMID: 27532257, 25765472, 24125834, 35653365, 35536239, 28491739, 36264615); Not observed at significant frequency in large population cohorts … (more)
Identified in patients with ARVC in published literature (PMID: 27532257, 25765472, 24125834, 35653365, 35536239, 28491739, 36264615); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27532257, 24125834, 36451335, 35536239, 25765472, 35653365, 28491739, 36264615, 31402444) (less)
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Arg355*) in the PKP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). This variant is present in population databases (rs754912778, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 24125834, 25765472, 27532257). ClinVar contains an entry for this variant (Variation ID: 201977). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant is predicted to result in loss of protein function through nonsense-mediated decay or protein truncation. Loss of function is an established mechanism of disease. It has been reported in multiple individuals with arrhythmogenic right ventricular cardiomyopathy or referred for cardiomyopathy genetic testing (PMID: 28491739, 25765472, 24125834, 27532257). This variant is rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).
Comment:
The p.Arg355X variant in PKP2 has been identified in 1 individual with ARVC (Bao 2013). This variant has also been identified in 1/8650 East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs754912778) and has been reported in ClinVar (Variation ID: 201977). This nonsense variant leads to a premature termination codon at position 355, which is predicted to lead to a truncated or absent protein. Frameshift and other truncating variants in PKP2 are strongly associated with ARVC. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg355X variant is likely pathogenic.
Comment:
The p.R355* pathogenic mutation (also known as c.1063C>T), located in coding exon 4 of the PKP2 gene, results from a C to T substitution at nucleotide position 1063. This changes the amino acid from an arginine to a stop codon within coding exon 4. This alteration has been reported in association with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Bao J et al. Circ Cardiovasc Genet, 2013 Dec;6:552-6; Zhou X et al. Eur J Med Genet, 2015 Apr;58:258-65; Castro SA et al. HeartRhythm Case Rep, 2016 Nov;2:469-472). This alteration has also been reported in biobank and whole exome sequencing cohorts (Haggerty CM et al. Genet Med, 2017 Nov;19:1245-1252; Xiao H et al. World J Pediatr, 2022 Oct;18:687-694; Bourfiss M et al. Circ Genom Precis Med, 2022 Dec;15:e003704). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
Identified in patients with ARVC in published literature (PMID: 27532257, 25765472, 24125834, 35653365, 35536239, 28491739, 36264615); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27532257, 24125834, 36451335, 35536239, 25765472, 35653365, 28491739, 36264615, 31402444)
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:
The nonsense c.3764C>G, p.Ala1255Gly variant identified in the MYBPC3 gene has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 24125834, 27532257, 25765472). This variant is absent in gnomAD v3.1.1, suggesting it is not a common benign variant in the populations represented in this database. The variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNAdecay. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). Based on available evidence, this variant is classified as Pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Arg355*) in the PKP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 23911551). This variant is present in population databases (rs754912778, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 24125834, 25765472, 27532257). ClinVar contains an entry for this variant (Variation ID: 201977). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant is predicted to result in loss of protein function through nonsense-mediated decay or protein truncation. Loss of function is an established mechanism of disease. It has been reported in multiple individuals with arrhythmogenic right ventricular cardiomyopathy or referred for cardiomyopathy genetic testing (PMID: 28491739, 25765472, 24125834, 27532257). This variant is rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).
Comment:
The p.Arg355X variant in PKP2 has been identified in 1 individual with ARVC (Bao 2013). This variant has also been identified in 1/8650 East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs754912778) and has been reported in ClinVar (Variation ID: 201977). This nonsense variant leads to a premature termination codon at position 355, which is predicted to lead to a truncated or absent protein. Frameshift and other truncating variants in PKP2 are strongly associated with ARVC. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg355X variant is likely pathogenic.
Comment:
The p.R355* pathogenic mutation (also known as c.1063C>T), located in coding exon 4 of the PKP2 gene, results from a C to T substitution at nucleotide position 1063. This changes the amino acid from an arginine to a stop codon within coding exon 4. This alteration has been reported in association with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Bao J et al. Circ Cardiovasc Genet, 2013 Dec;6:552-6; Zhou X et al. Eur J Med Genet, 2015 Apr;58:258-65; Castro SA et al. HeartRhythm Case Rep, 2016 Nov;2:469-472). This alteration has also been reported in biobank and whole exome sequencing cohorts (Haggerty CM et al. Genet Med, 2017 Nov;19:1245-1252; Xiao H et al. World J Pediatr, 2022 Oct;18:687-694; Bourfiss M et al. Circ Genom Precis Med, 2022 Dec;15:e003704). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
Identified in patients with ARVC in published literature (PMID: 27532257, 25765472, 24125834, 35653365, 35536239, 28491739, 36264615); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27532257, 24125834, 36451335, 35536239, 25765472, 35653365, 28491739, 36264615, 31402444)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Prevalence and Disease Expression of Pathogenic and Likely Pathogenic Variants Associated With Inherited Cardiomyopathies in the General Population. | Bourfiss M | Circulation. Genomic and precision medicine | 2022 | PMID: 36264615 |
| Secondary genomic findings in the 2020 China Neonatal Genomes Project participants. | Xiao H | World journal of pediatrics : WJP | 2022 | PMID: 35727495 |
| Molecular genetics in 4408 cardiomyopathy probands and 3008 relatives in Norway: 17 years of genetic testing in a national laboratory. | Stava TT | European journal of preventive cardiology | 2022 | PMID: 35653365 |
| Population Prevalence of Premature Truncating Variants in Plakophilin-2 and Association With Arrhythmogenic Right Ventricular Cardiomyopathy: A UK Biobank Analysis. | Hylind RJ | Circulation. Genomic and precision medicine | 2022 | PMID: 35536239 |
| Electronic health record phenotype in subjects with genetic variants associated with arrhythmogenic right ventricular cardiomyopathy: a study of 30,716 subjects with exome sequencing. | Haggerty CM | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28471438 |
| 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 |
| Incremental value of electroanatomical mapping for the diagnosis of arrhythmogenic right ventricular cardiomyopathy in a patient with sustained ventricular tachycardia. | Castro SA | HeartRhythm case reports | 2016 | PMID: 28491739 |
| Comprehensive analysis of desmosomal gene mutations in Han Chinese patients with arrhythmogenic right ventricular cardiomyopathy. | Zhou X | European journal of medical genetics | 2015 | PMID: 25765472 |
| Correlation of ventricular arrhythmias with genotype in arrhythmogenic right ventricular cardiomyopathy. | Bao J | Circulation. Cardiovascular genetics | 2013 | PMID: 24125834 |
| Mechanistic basis of desmosome-targeted diseases. | Al-Jassar C | Journal of molecular biology | 2013 | PMID: 23911551 |
| Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. | Gerull B | Nature genetics | 2004 | PMID: 15489853 |
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Text-mined citations for rs754912778 ...
HelpThese 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 Sep 29, 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.