VCV000180472.10 - ClinVar

NM_001005242.3(PKP2):c.1045A>G (p.Met349Val)

Germline

Classification

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

Uncertain significance

4 out of 5 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.1045A>G (p.Met349Val)

Variation ID: 180472 Accession: VCV000180472.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12p11.21 12: 32869052 (GRCh38) [ NCBI UCSC ] 12: 33021986 (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	Feb 7, 2015	Feb 15, 2026	Jul 10, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001005242.3:c.1045A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001005242.2:p.Met349Val	missense
NM_004572.4:c.1045A>G	NP_004563.2:p.Met349Val	missense
NC_000012.12:g.32869052T>C
NC_000012.11:g.33021986T>C
NG_009000.1:g.32795A>G
LRG_398:g.32795A>G
LRG_398t1:c.1045A>G	LRG_398p1:p.Met349Val

... more HGVS ... less HGVS

Protein change

M349V

Other names

Canonical SPDI

NC_000012.12:32869051:T:C

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00003

Links

ClinGen: CA010717 dbSNP: rs199957846 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	2347	2406

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.
Primary familial hypertrophic cardiomyopathy	Uncertain significance (1)	no assertion criteria provided	Nov 27, 2014	RCV000157410.1
not provided	Uncertain significance (1)	criteria provided, single submitter	Jun 24, 2013	RCV000172091.2
Arrhythmogenic right ventricular dysplasia 9	Uncertain significance (1)	criteria provided, single submitter	Jun 13, 2022	RCV002515050.5
Cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Jun 13, 2024	RCV003531991.2
Arrhythmogenic right ventricular cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Jul 10, 2024	RCV003998336.3

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.
Uncertain significance (Jun 24, 2013) C Contributing to aggregate classification	criteria provided, single submitter (Ng et al. (Circ Cardiovasc Genet. 2013))	not provided	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000054795.1 First in ClinVar: Jun 08, 2015 Last updated: Jun 08, 2015 Comments (2): Medical sequencing The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for … (more) The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for details. (less)	Observation: 1 Collection method: research Allele origin: unknown Affected status: unknown more Observation 1 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Platform type: next-gen sequencing

Uncertain Significance (Jul 10, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Arrhythmogenic right ventricular cardiomyopathy (Autosomal dominant inheritance)	All of Us Research Program, National Institutes of Health Accession: SCV004832516.2 First in ClinVar: Apr 20, 2024 Last updated: Dec 14, 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: show This missense variant replaces methionine with valine at codon 349 of the PKP2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PKP2-related disorders in the literature. This variant has been identified in 10/282680 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 2 Zygosity: Single Heterozygote

Uncertain significance (Jun 13, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	Color Diagnostics, LLC DBA Color Health Accession: SCV004358902.2 First in ClinVar: Feb 14, 2024 Last updated: May 03, 2025	Comment: show This missense variant replaces methionine with valine at codon 349 of the PKP2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PKP2-related disorders in the literature. This variant has been identified in 10/282680 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Platform type: NGS

Uncertain significance (Jun 13, 2022) 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: SCV002933158.4 First in ClinVar: Feb 07, 2023 Last updated: Feb 15, 2026	Comment: show In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 180472). This variant has not been reported in the literature in individuals affected with PKP2-related conditions. This variant is present in population databases (rs199957846, gnomAD 0.02%). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 349 of the PKP2 protein (p.Met349Val). (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

Uncertain significance (Nov 27, 2014) N Not contributing to aggregate classification	no assertion criteria provided	Primary familial hypertrophic cardiomyopathy	Blueprint Genetics Accession: SCV000207149.1 First in ClinVar: Feb 07, 2015 Last updated: Feb 07, 2015	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1

Comment:

This missense variant replaces methionine with valine at codon 349 of the PKP2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PKP2-related disorders in the literature. This variant has been identified in 10/282680 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:

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 180472). This variant has not been reported in the literature in individuals affected with PKP2-related conditions. This variant is present in population databases (rs199957846, gnomAD 0.02%). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 349 of the PKP2 protein (p.Met349Val).

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs199957846 ...

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 Mar 08, 2026