VCV000200321.12 - ClinVar

NM_000238.4(KCNH2):c.1096C>T (p.Arg366Ter)

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.

(5)

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

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.1096C>T (p.Arg366Ter)

Variation ID: 200321 Accession: VCV000200321.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q36.1 7: 150654411 (GRCh37) [ NCBI UCSC ] 7: 150957323 (GRCh38) [ 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	Jul 23, 2024	Mar 19, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000238.4:c.1096C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000229.1:p.Arg366Ter	nonsense
NM_001406753.1:c.808C>T	NP_001393682.1:p.Arg270Ter	nonsense
NM_001406755.1:c.919C>T	NP_001393684.1:p.Arg307Ter	nonsense
NM_001406756.1:c.808C>T	NP_001393685.1:p.Arg270Ter	nonsense
NM_001406757.1:c.796C>T	NP_001393686.1:p.Arg266Ter	nonsense
NM_172056.3:c.1096C>T	NP_742053.1:p.Arg366Ter	nonsense
NR_176254.1:n.1504C>T
NC_000007.14:g.150957323G>A
NC_000007.13:g.150654411G>A
NG_008916.1:g.25604C>T
LRG_288:g.25604C>T
LRG_288t1:c.1096C>T	LRG_288p1:p.Arg366Ter
LRG_288t2:c.1096C>T	LRG_288p2:p.Arg366Ter

... more HGVS ... less HGVS

Protein change

R366*, R266*, R307*, R270*

Other names

p.R366*:CGA>TGA

Canonical SPDI

NC_000007.14:150957322: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.

Links

ClinGen: CA004210 dbSNP: rs794728364 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.
not provided	Pathogenic (1)	criteria provided, single submitter	Mar 19, 2024	RCV000181779.5
Long QT syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 2, 2023	RCV001039878.6
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Nov 27, 2023	RCV002453650.2
Long QT syndrome 2	Pathogenic (1)	criteria provided, single submitter	Jul 5, 2023	RCV003327377.1

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 (Mar 19, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000234082.9 First in ClinVar: Jul 05, 2015 Last updated: Jul 23, 2024	Comment: 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 … (more) 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19038855, 25525159, 24606995, 15840476, 18808722, 31382961, 31440721, 31737537, 11468227) (less)
Pathogenic (Jul 05, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Long QT syndrome 2 Affected status: yes Allele origin: unknown	KardioGenetik, Herz- und Diabeteszentrum NRW Accession: SCV004034989.1 First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023	Number of individuals with the variant: 1
Pathogenic (Oct 02, 2023)	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: SCV001203428.3 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 10973849‚ 19862833‚ 11468227‚ 23158531‚ 24606995 Comment: This sequence change creates a premature translational stop signal (p.Arg366) in the KCNH2 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg366) in the KCNH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 10973849, 19862833). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with long QT syndrome (LQTS) (PMID: 11468227, 23158531, 24606995). ClinVar contains an entry for this variant (Variation ID: 200321). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Aug 23, 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: SCV004829921.1 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 (7) PubMed: 11468227‚ 15840476‚ 18808722‚ 19038855‚ 23158531‚ 29020304‚ 36102233 Comment: This variant changes 1 nucleotide in exon 5 of the KCNH2 gene, creating a premature translation stop signal. This variant is expected to result in … (more) This variant changes 1 nucleotide in exon 5 of the KCNH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with or suspected of long QT syndrome (PMID: 11468227, 15840476, 18808722, 19038855, 23158531, 29020304, 36102233). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less) Number of individuals with the variant: 1
Pathogenic (Nov 27, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002738529.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 11468227‚ 15840476‚ 18808722‚ 24606995 Comment: The p.R366* pathogenic mutation (also known as c.1096C>T), located in coding exon 5 of the KCNH2 gene, results from a C to T substitution at … (more) The p.R366* pathogenic mutation (also known as c.1096C>T), located in coding exon 5 of the KCNH2 gene, results from a C to T substitution at nucleotide position 1096. This changes the amino acid from an arginine to a stop codon within coding exon 5. This mutation has been reported in multiple individuals with long QT syndrome (Larsen LA et al. Clin. Chem., 2001 Aug;47:1390-5; Christiansen M et al. BMC Med. Genet., 2014 Mar;15:31; Zhang X et al. BMC Med. Genet., 2008 Sep;9:87; Tester DJ et al. Heart Rhythm, 2005 May;2:507-17). 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)

Comment:

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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19038855, 25525159, 24606995, 15840476, 18808722, 31382961, 31440721, 31737537, 11468227)

Comment:

This sequence change creates a premature translational stop signal (p.Arg366*) in the KCNH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 10973849, 19862833). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with long QT syndrome (LQTS) (PMID: 11468227, 23158531, 24606995). ClinVar contains an entry for this variant (Variation ID: 200321). For these reasons, this variant has been classified as Pathogenic.

Comment:

This variant changes 1 nucleotide in exon 5 of the KCNH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with or suspected of long QT syndrome (PMID: 11468227, 15840476, 18808722, 19038855, 23158531, 29020304, 36102233). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

Comment:

The p.R366* pathogenic mutation (also known as c.1096C>T), located in coding exon 5 of the KCNH2 gene, results from a C to T substitution at nucleotide position 1096. This changes the amino acid from an arginine to a stop codon within coding exon 5. This mutation has been reported in multiple individuals with long QT syndrome (Larsen LA et al. Clin. Chem., 2001 Aug;47:1390-5; Christiansen M et al. BMC Med. Genet., 2014 Mar;15:31; Zhang X et al. BMC Med. Genet., 2008 Sep;9:87; Tester DJ et al. Heart Rhythm, 2005 May;2:507-17). 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.

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
Sex Differences and Utility of Treadmill Testing in Long-QT Syndrome.	Yee LA	Journal of the American Heart Association	2022	PMID: 36102233
Identification of a targeted and testable antiarrhythmic therapy for long-QT syndrome type 2 using a patient-specific cellular model.	Mehta A	European heart journal	2018	PMID: 29020304
Mutations in Danish patients with long QT syndrome and the identification of a large founder family with p.F29L in KCNH2.	Christiansen M	BMC medical genetics	2014	PMID: 24606995
Vagal reflexes following an exercise stress test: a simple clinical tool for gene-specific risk stratification in the long QT syndrome.	Crotti L	Journal of the American College of Cardiology	2012	PMID: 23158531
The genetic basis of long QT and short QT syndromes: a mutation update.	Hedley PL	Human mutation	2009	PMID: 19862833
Identification of a possible pathogenic link between congenital long QT syndrome and epilepsy.	Johnson JN	Neurology	2009	PMID: 19038855
Protective effect of KCNH2 single nucleotide polymorphism K897T in LQTS families and identification of novel KCNQ1 and KCNH2 mutations.	Zhang X	BMC medical genetics	2008	PMID: 18808722
Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing.	Tester DJ	Heart rhythm	2005	PMID: 15840476
Screening for mutations and polymorphisms in the genes KCNH2 and KCNE2 encoding the cardiac HERG/MiRP1 ion channel: implications for acquired and congenital long Q-T syndrome.	Larsen LA	Clinical chemistry	2001	PMID: 11468227
Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.	Splawski I	Circulation	2000	PMID: 10973849

Text-mined citations for rs794728364 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000238.4(KCNH2):c.1096C>T (p.Arg366Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs794728364 ...