VCV002774100.3 - ClinVar

NM_001005242.3(PKP2):c.1202T>A (p.Leu401Gln)

Germline

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.

(3)

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.

Uncertain significance

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.1202T>A (p.Leu401Gln)

Variation ID: 2774100 Accession: VCV002774100.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12p11.21 12: 32850942 (GRCh38) [ NCBI UCSC ] 12: 33003876 (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 14, 2024	Aug 11, 2024	Apr 12, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001005242.3:c.1202T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001005242.2:p.Leu401Gln	missense
NM_001407155.1:c.1202T>A	NP_001394084.1:p.Leu401Gln	missense
NM_001407156.1:c.1202T>A	NP_001394085.1:p.Leu401Gln	missense
NM_001407157.1:c.1202T>A	NP_001394086.1:p.Leu401Gln	missense
NM_001407158.1:c.875T>A	NP_001394087.1:p.Leu292Gln	missense
NM_001407159.1:c.875T>A	NP_001394088.1:p.Leu292Gln	missense
NM_001407160.1:c.875T>A	NP_001394089.1:p.Leu292Gln	missense
NM_001407161.1:c.1202T>A	NP_001394090.1:p.Leu401Gln	missense
NM_001407162.1:c.875T>A	NP_001394091.1:p.Leu292Gln	missense
NM_004572.4:c.1202T>A	NP_004563.2:p.Leu401Gln	missense
NC_000012.12:g.32850942A>T
NC_000012.11:g.33003876A>T
NG_009000.1:g.50905T>A
LRG_398:g.50905T>A
LRG_398t1:c.1202T>A	LRG_398p1:p.Leu401Gln

... more HGVS ... less HGVS

Protein change

L401Q, L292Q

Other names

Canonical SPDI

NC_000012.12:32850941:A:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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.

Links

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	1942	1995

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.
Cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	May 17, 2023	RCV003532779.1
Arrhythmogenic right ventricular cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Jun 8, 2023	RCV004011532.2
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Apr 12, 2024	RCV004654269.1

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.
Uncertain significance (May 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV004358895.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Comment: This missense variant replaces leucine with glutamine at codon 401 of the PKP2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more) This missense variant replaces leucine with glutamine at codon 401 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/251286 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)
Uncertain Significance (Jun 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV004846419.1 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 missense variant replaces leucine with glutamine at codon 401 of the PKP2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more) This missense variant replaces leucine with glutamine at codon 401 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/251286 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) Number of individuals with the variant: 1
Uncertain significance (Apr 12, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005155384.1 First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024	Comment: The p.L401Q variant (also known as c.1202T>A), located in coding exon 5 of the PKP2 gene, results from a T to A substitution at nucleotide … (more) The p.L401Q variant (also known as c.1202T>A), located in coding exon 5 of the PKP2 gene, results from a T to A substitution at nucleotide position 1202. The leucine at codon 401 is replaced by glutamine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. (less)

Comment:

This missense variant replaces leucine with glutamine at codon 401 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/251286 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:

The p.L401Q variant (also known as c.1202T>A), located in coding exon 5 of the PKP2 gene, results from a T to A substitution at nucleotide position 1202. The leucine at codon 401 is replaced by glutamine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

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:

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 this variant ...

Record last updated Aug 11, 2024

ClinVar Genomic variation as it relates to human health

NM_001005242.3(PKP2):c.1202T>A (p.Leu401Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...