VCV000067493.4 - ClinVar

NM_000238.4(KCNH2):c.3404G>A (p.Arg1135His)

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.3404G>A (p.Arg1135His)

Variation ID: 67493 Accession: VCV000067493.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q36.1 7: 150945441 (GRCh38) [ NCBI UCSC ] 7: 150642529 (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	Oct 9, 2016	Feb 7, 2023	Sep 2, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000238.4:c.3404G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000229.1:p.Arg1135His	missense
NM_172057.3:c.2384G>A	NP_742054.1:p.Arg795His	missense
NC_000007.14:g.150945441C>T
NC_000007.13:g.150642529C>T
NG_008916.1:g.37486G>A
LRG_288:g.37486G>A
LRG_288t1:c.3404G>A	LRG_288p1:p.Arg1135His

... more HGVS ... less HGVS

Protein change

R1135H, R795H

Other names

Canonical SPDI

NC_000007.14:150945440:C: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.

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA008277 dbSNP: rs199473547 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	3230	3316

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.
Short QT syndrome	not provided (1)	no classification provided	-	RCV000058222.3
not provided	Uncertain significance (1)	criteria provided, single submitter	Feb 18, 2022	RCV002223783.1
Long QT syndrome	Uncertain significance (1)	criteria provided, single submitter	Sep 2, 2022	RCV002514289.2

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.	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 (Sep 02, 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: SCV003441182.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 18692916 Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1135 of the KCNH2 protein (p.Arg1135His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1135 of the KCNH2 protein (p.Arg1135His). This variant is present in population databases (rs199473547, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of KCNH2-related conditions (PMID: 18692916). ClinVar contains an entry for this variant (Variation ID: 67493). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 18692916). 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 (Feb 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002502048.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (2) PubMed: 18692916‚ 19174314 Number of individuals with the variant: 1 Secondary finding: no
not provided (-)	no classification provided Method: literature only	Short QT syndrome Affected status: unknown Allele origin: germline	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust Accession: SCV000089742.3 First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016	Publications: PubMed (3) PubMed: 22581653‚ 18692916‚ 19174314 Comment: This variant has been reported as associated with Short QT syndrome in the following publications (PMID:18692916;PMID:19174314). This is a literature report, and does not necessarily … (more) This variant has been reported as associated with Short QT syndrome in the following publications (PMID:18692916;PMID:19174314). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. (less)

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1135 of the KCNH2 protein (p.Arg1135His). This variant is present in population databases (rs199473547, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of KCNH2-related conditions (PMID: 18692916). ClinVar contains an entry for this variant (Variation ID: 67493). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 18692916). 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 variant has been reported as associated with Short QT syndrome in the following publications (PMID:18692916;PMID:19174314). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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
Role of the R1135H KCNH2 mutation in Brugada syndrome.	Wilders R	International journal of cardiology	2010	PMID: 19174314
A novel KCNH2 mutation as a modifier for short QT interval.	Itoh H	International journal of cardiology	2009	PMID: 18692916

Text-mined citations for rs199473547 ...

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.3404G>A (p.Arg1135His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs199473547 ...