NM_000238.4(KCNH2):c.2350C>T (p.Arg784Trp) AND Long QT syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 15, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001851875.12

Allele description [Variation Report for NM_000238.4(KCNH2):c.2350C>T (p.Arg784Trp)]

NM_000238.4(KCNH2):c.2350C>T (p.Arg784Trp)

Gene:

KCNH2:potassium voltage-gated channel subfamily H member 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q36.1

Genomic location:

Preferred name:

NM_000238.4(KCNH2):c.2350C>T (p.Arg784Trp)

HGVS:

NC_000007.14:g.150950216G>A
NG_008916.1:g.32711C>T
NM_000238.4:c.2350C>TMANE SELECT
NM_001204798.2:c.1330C>T
NM_001406753.1:c.2062C>T
NM_001406755.1:c.2173C>T
NM_001406756.1:c.2062C>T
NM_001406757.1:c.2050C>T
NM_172056.3:c.2350C>T
NM_172057.3:c.1330C>T
NP_000229.1:p.Arg784Trp
NP_000229.1:p.Arg784Trp
NP_001191727.1:p.Arg444Trp
NP_001393682.1:p.Arg688Trp
NP_001393684.1:p.Arg725Trp
NP_001393685.1:p.Arg688Trp
NP_001393686.1:p.Arg684Trp
NP_742053.1:p.Arg784Trp
NP_742053.1:p.Arg784Trp
NP_742054.1:p.Arg444Trp
NP_742054.1:p.Arg444Trp
LRG_288t1:c.2350C>T
LRG_288t2:c.2350C>T
LRG_288t3:c.1330C>T
LRG_288:g.32711C>T
LRG_288p1:p.Arg784Trp
LRG_288p2:p.Arg784Trp
LRG_288p3:p.Arg444Trp
NC_000007.13:g.150647304G>A
NM_000238.3:c.2350C>T
NM_172056.2:c.2350C>T
NM_172057.2:c.1330C>T
NR_176254.1:n.2758C>T
NR_176255.1:n.1631C>T
Q12809:p.Arg784Trp

Protein change:

R444W; ARG784TRP

Links:

UniProtKB: Q12809#VAR_036676; OMIM: 152427.0014; dbSNP: rs12720441

NCBI 1000 Genomes Browser:

rs12720441

Molecular consequence:

NM_000238.4:c.2350C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001204798.2:c.1330C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.2062C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.2173C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.2062C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.2050C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.2350C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.1330C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Long QT syndrome (LQTS)
Identifiers:: MONDO: MONDO:0002442; MeSH: D008133; MedGen: C0023976

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002205738	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 13, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 15840476, 19841300, 22949429, 11997281, 25417810, 28492532
SCV004843913	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Aug 15, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 11997281, 15840476, 19172259, 19841300, 22949429, 24223155, 25417810, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002205738

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 13, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV004843913

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Aug 15, 2023)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	4	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes.

Yang P, Kanki H, Drolet B, Yang T, Wei J, Viswanathan PC, Hohnloser SH, Shimizu W, Schwartz PJ, Stanton M, Murray KT, Norris K, George AL Jr, Roden DM.

Circulation. 2002 Apr 23;105(16):1943-8.

PubMed [citation]

PMID:: 11997281

See all PubMed Citations (9)

Details of each submission

From Invitae, SCV002205738.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 784 of the KCNH2 protein (p.Arg784Trp). This variant is present in population databases (rs12720441, gnomAD 0.002%). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 11997281, 15840476, 19841300, 22949429). ClinVar contains an entry for this variant (Variation ID: 14433). 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"). Experimental studies have shown that this missense change affects KCNH2 function (PMID: 11997281, 25417810). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004843913.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (8)

Description

This missense variant replaces arginine with tryptophan at codon 784 of the KCNH2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). In vitro experimental functional studies have shown that this variant may result in deficient protein trafficking (PMID: 25417810), reduced channel current (PMID: 11997281) and faster channel deactivation compared to wild type (PMID: 19172259). This variant has been reported in two individuals affected with long QT syndrome (PMID: 19841300, 22949429) and in an individual suspected to be affected with long QT syndrome (PMID: 15840476). This variant has also been reported in two individuals affected with drug-induced torsades de pointes, a form of ventricular tachycardia (PMID: 11997281, 24223155). This variant has been identified in 3/282186 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		4	not provided	not provided	not provided

Last Updated: Sep 16, 2024

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