NM_000238.4(KCNH2):c.2371C>T (p.Arg791Trp) AND Long QT syndrome

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Feb 5, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000148535.21

Allele description [Variation Report for NM_000238.4(KCNH2):c.2371C>T (p.Arg791Trp)]

NM_000238.4(KCNH2):c.2371C>T (p.Arg791Trp)

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.2371C>T (p.Arg791Trp)

Other names:

p.R791W:CGG>TGG

HGVS:

NC_000007.14:g.150950195G>A
NG_008916.1:g.32732C>T
NM_000238.4:c.2371C>TMANE SELECT
NM_001204798.2:c.1351C>T
NM_001406753.1:c.2083C>T
NM_001406755.1:c.2194C>T
NM_001406756.1:c.2083C>T
NM_001406757.1:c.2071C>T
NM_172056.3:c.2371C>T
NM_172057.3:c.1351C>T
NP_000229.1:p.Arg791Trp
NP_000229.1:p.Arg791Trp
NP_001191727.1:p.Arg451Trp
NP_001393682.1:p.Arg695Trp
NP_001393684.1:p.Arg732Trp
NP_001393685.1:p.Arg695Trp
NP_001393686.1:p.Arg691Trp
NP_742053.1:p.Arg791Trp
NP_742053.1:p.Arg791Trp
NP_742054.1:p.Arg451Trp
NP_742054.1:p.Arg451Trp
LRG_288t1:c.2371C>T
LRG_288t2:c.2371C>T
LRG_288t3:c.1351C>T
LRG_288:g.32732C>T
LRG_288p1:p.Arg791Trp
LRG_288p2:p.Arg791Trp
LRG_288p3:p.Arg451Trp
NC_000007.13:g.150647283G>A
NM_000238.2:c.2371C>T
NM_000238.3:c.2371C>T
NM_172056.2:c.2371C>T
NM_172057.2:c.1351C>T
NR_176254.1:n.2779C>T
NR_176255.1:n.1652C>T
Q12809:p.Arg791Trp

Protein change:

R451W

Links:

UniProtKB: Q12809#VAR_074879; dbSNP: rs138498207

NCBI 1000 Genomes Browser:

rs138498207

Molecular consequence:

NM_000238.4:c.2371C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001204798.2:c.1351C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.2083C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.2194C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.2083C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.2071C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.2371C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.1351C>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

variation affecting protein function [Variation Ontology: 0003]

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
SCV000055275	Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq	criteria provided, single submitter (Ng et al. (Circ Cardiovasc Genet. 2013))	Likely benign (Jun 24, 2013)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV000190248	CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation	no assertion criteria provided	Uncertain significance (Jun 1, 2014)	germline	research
SCV000752905	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Jan 27, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004843910	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Feb 5, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25417810, 29752375, 31521807, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	13	not provided	not provided	108544	not provided	clinical testing, research
not provided	unknown	unknown	1	not provided	not provided	not provided	not provided	research

Citations

PubMed

Interpreting secondary cardiac disease variants in an exome cohort.

Ng D, Johnston JJ, Teer JK, Singh LN, Peller LC, Wynter JS, Lewis KL, Cooper DN, Stenson PD, Mullikin JC, Biesecker LG; NIH Intramural Sequencing Center (NISC) Comparative Sequencing Program..

Circ Cardiovasc Genet. 2013 Aug;6(4):337-46. doi: 10.1161/CIRCGENETICS.113.000039. Epub 2013 Jul 16.

PubMed [citation]

PMID:: 23861362
PMCID:: PMC3887521

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

See all PubMed Citations (6)

Details of each submission

From Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq, SCV000055275.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (1)

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

From CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190248.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000752905.7

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

#	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, SCV004843910.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	13	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces arginine with tryptophan at codon 791 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). Functional studies have shown that this variant altered Kv11.1 channel activation and deactivation (PMID: 25417810, 29752375). This variant has been reported in one case of sudden infant death syndrome (PMID: 29752375) and one individual with long QT syndrome (PMID: 31521807 ). This variant has been identified in 25/281704 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		13	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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