VCV000237296.12 - ClinVar

NM_000238.4(KCNH2):c.2291C>T (p.Pro764Leu)

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_000238.4(KCNH2):c.2291C>T (p.Pro764Leu)

Variation ID: 237296 Accession: VCV000237296.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q36.1 7: 150950275 (GRCh38) [ NCBI UCSC ] 7: 150647363 (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	Dec 26, 2017	Apr 20, 2024	Nov 30, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000238.4:c.2291C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000229.1:p.Pro764Leu	missense
NM_001204798.2:c.1271C>T	NP_001191727.1:p.Pro424Leu	missense
NM_001406753.1:c.2003C>T	NP_001393682.1:p.Pro668Leu	missense
NM_001406755.1:c.2114C>T	NP_001393684.1:p.Pro705Leu	missense
NM_001406756.1:c.2003C>T	NP_001393685.1:p.Pro668Leu	missense
NM_001406757.1:c.1991C>T	NP_001393686.1:p.Pro664Leu	missense
NM_172056.3:c.2291C>T	NP_742053.1:p.Pro764Leu	missense
NM_172057.3:c.1271C>T	NP_742054.1:p.Pro424Leu	missense
NR_176254.1:n.2699C>T
NR_176255.1:n.1572C>T
NC_000007.14:g.150950275G>A
NC_000007.13:g.150647363G>A
NG_008916.1:g.32652C>T
LRG_288:g.32652C>T
LRG_288t1:c.2291C>T	LRG_288p1:p.Pro764Leu
LRG_288t2:c.2291C>T	LRG_288p2:p.Pro764Leu
LRG_288t3:c.1271C>T	LRG_288p3:p.Pro424Leu

... more HGVS ... less HGVS

Protein change

P424L, P764L, P664L, P668L, P705L

Other names

Canonical SPDI

NC_000007.14:150950274:G:A

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA10582466 dbSNP: rs878853773 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.
KCNH2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3223	3309

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.
Long QT syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Nov 30, 2023	RCV000227941.16
Cardiac arrhythmia	Uncertain significance (1)	criteria provided, single submitter	Jun 9, 2023	RCV001842994.11

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 (Jul 19, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Long QT syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000283971.5 First in ClinVar: Jul 03, 2016 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 23631430 Comment: This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 764 of the KCNH2 protein (p.Pro764Leu). … (more) This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 764 of the KCNH2 protein (p.Pro764Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with a suspected diagnosis of long QT syndrome (PMID: 23631430). ClinVar contains an entry for this variant (Variation ID: 237296). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. (less)
Uncertain significance (Jun 09, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiac arrhythmia Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001349873.3 First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 23631430 Comment: This missense variant replaces proline with leucine at codon 764 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more) This missense variant replaces proline with leucine at codon 764 of the KCNH2 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual referred for long QT syndrome genetic testing (PMID: 23631430). This variant has not been identified 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 (Nov 30, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Long QT syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004843915.1 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)	Publications: PubMed (1) PubMed: 23631430 Comment: This missense variant replaces proline with leucine at codon 764 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more) This missense variant replaces proline with leucine at codon 764 of the KCNH2 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual referred for long QT syndrome genetic testing (PMID: 23631430). This variant has not been identified 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: 4

Comment:

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 764 of the KCNH2 protein (p.Pro764Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with a suspected diagnosis of long QT syndrome (PMID: 23631430). ClinVar contains an entry for this variant (Variation ID: 237296). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

Comment:

This missense variant replaces proline with leucine at codon 764 of the KCNH2 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual referred for long QT syndrome genetic testing (PMID: 23631430). This variant has not been identified 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:

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

Title	Author	Journal	Year	Link
Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory.	Lieve KV	Genetic testing and molecular biomarkers	2013	PMID: 23631430

Text-mined citations for rs878853773 ...

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 Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000238.4(KCNH2):c.2291C>T (p.Pro764Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs878853773 ...