VCV000188658.13 - ClinVar

NM_001005242.3(PKP2):c.1177C>T (p.Gln393Ter)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

4 out of 4 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.1177C>T (p.Gln393Ter)

Variation ID: 188658 Accession: VCV000188658.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12p11.21 12: 32850967 (GRCh38) [ NCBI UCSC ] 12: 33003901 (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 10, 2021	Feb 15, 2026	Aug 28, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001005242.3:c.1177C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001005242.2:p.Gln393Ter	nonsense
NM_004572.4:c.1177C>T	NP_004563.2:p.Gln393Ter	nonsense
NC_000012.12:g.32850967G>A
NC_000012.11:g.33003901G>A
NG_009000.1:g.50880C>T
LRG_398:g.50880C>T
LRG_398t1:c.1177C>T	LRG_398p1:p.Gln393Ter

... more HGVS ... less HGVS

Protein change

Q393*

Other names

Canonical SPDI

NC_000012.12:32850966:G:A

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.

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

The Genome Aggregation Database (gnomAD), exomes 0.00000

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Links

ClinGen: CA010892 dbSNP: rs786204393 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	2356	2416

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 dysplasia 9	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Aug 28, 2024	RCV001389963.10
not provided	Likely pathogenic (1)	criteria provided, single submitter	Nov 5, 2021	RCV001778768.2
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Aug 30, 2019	RCV002326930.2

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.
Pathogenic (Aug 28, 2024) 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: SCV001591525.6 First in ClinVar: May 10, 2021 Last updated: Feb 15, 2026	Publications: PubMed (5) PubMed: 15489853‚ 17041889‚ 23812740‚ 23911551‚ 27532257 Comment: show This sequence change creates a premature translational stop signal (p.Gln393*) 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, 17041889, 23911551). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of arrhythmogenic right ventricular cardiomyopathy (PMID: 23812740, 27532257). ClinVar contains an entry for this variant (Variation ID: 188658). For these reasons, this variant has been classified as 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 (Nov 05, 2021) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV002015761.2 First in ClinVar: Nov 20, 2021 Last updated: Mar 04, 2023	Comment: show Reported in association with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Baskin et al., 2013; Walsh et al., 2017); Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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, 23812740, 31402444, 26582918) (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

Pathogenic (Aug 30, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV002637582.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 23812740‚ 27532257 Comment: show The p.Q393* pathogenic mutation (also known as c.1177C>T), located in coding exon 5 of the PKP2 gene, results from a C to T substitution at nucleotide position 1177. This changes the amino acid from a glutamine to a stop codon within coding exon 5. This alteration has been reported in association with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Baskin B et al. Hum. Genet., 2013 Nov;132:1245-52; Walsh R et al. Genet. Med., 2017 02;19:192-203). 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) 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 25, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Arrhythmogenic right ventricular dysplasia 9	Fulgent Genetics, Fulgent Genetics Accession: SCV005635007.1 First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 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

Comment:

This sequence change creates a premature translational stop signal (p.Gln393*) 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, 17041889, 23911551). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of arrhythmogenic right ventricular cardiomyopathy (PMID: 23812740, 27532257). ClinVar contains an entry for this variant (Variation ID: 188658). For these reasons, this variant has been classified as Pathogenic.

Comment:

Reported in association with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Baskin et al., 2013; Walsh et al., 2017); Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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, 23812740, 31402444, 26582918)

Comment:

The p.Q393* pathogenic mutation (also known as c.1177C>T), located in coding exon 5 of the PKP2 gene, results from a C to T substitution at nucleotide position 1177. This changes the amino acid from a glutamine to a stop codon within coding exon 5. This alteration has been reported in association with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Baskin B et al. Hum. Genet., 2013 Nov;132:1245-52; Walsh R et al. Genet. Med., 2017 02;19:192-203). 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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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
Mechanistic basis of desmosome-targeted diseases.	Al-Jassar C	Journal of molecular biology	2013	PMID: 23911551
TMEM43 mutations associated with arrhythmogenic right ventricular cardiomyopathy in non-Newfoundland populations.	Baskin B	Human genetics	2013	PMID: 23812740
Recessive arrhythmogenic right ventricular dysplasia due to novel cryptic splice mutation in PKP2.	Awad MM	Human mutation	2006	PMID: 17041889
Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy.	Gerull B	Nature genetics	2004	PMID: 15489853

Text-mined citations for rs786204393 ...

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 Feb 15, 2026