NM_000238.4(KCNH2):c.2320G>T (p.Asp774Tyr) AND Long QT syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 8, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003531958.2

Allele description [Variation Report for NM_000238.4(KCNH2):c.2320G>T (p.Asp774Tyr)]

NM_000238.4(KCNH2):c.2320G>T (p.Asp774Tyr)

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.2320G>T (p.Asp774Tyr)

Other names:

p.D774Y:GAC>TAC

HGVS:

NC_000007.14:g.150950246C>A
NG_008916.1:g.32681G>T
NM_000238.4:c.2320G>TMANE SELECT
NM_001204798.2:c.1300G>T
NM_001406753.1:c.2032G>T
NM_001406755.1:c.2143G>T
NM_001406756.1:c.2032G>T
NM_001406757.1:c.2020G>T
NM_172056.3:c.2320G>T
NM_172057.3:c.1300G>T
NP_000229.1:p.Asp774Tyr
NP_000229.1:p.Asp774Tyr
NP_001191727.1:p.Asp434Tyr
NP_001393682.1:p.Asp678Tyr
NP_001393684.1:p.Asp715Tyr
NP_001393685.1:p.Asp678Tyr
NP_001393686.1:p.Asp674Tyr
NP_742053.1:p.Asp774Tyr
NP_742053.1:p.Asp774Tyr
NP_742054.1:p.Asp434Tyr
NP_742054.1:p.Asp434Tyr
LRG_288t1:c.2320G>T
LRG_288t2:c.2320G>T
LRG_288t3:c.1300G>T
LRG_288:g.32681G>T
LRG_288p1:p.Asp774Tyr
LRG_288p2:p.Asp774Tyr
LRG_288p3:p.Asp434Tyr
NC_000007.13:g.150647334C>A
NM_000238.2:c.2320G>T
NM_000238.3:c.2320G>T
NM_172056.2:c.2320G>T
NM_172057.2:c.1300G>T
NR_176254.1:n.2728G>T
NR_176255.1:n.1601G>T
Q12809:p.Asp774Tyr

Protein change:

D434Y

Links:

UniProtKB: Q12809#VAR_068277; dbSNP: rs199472995

NCBI 1000 Genomes Browser:

rs199472995

Molecular consequence:

NM_000238.4:c.2320G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001204798.2:c.1300G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.2032G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.2143G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.2032G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.2020G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.2320G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.1300G>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV004294710	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 8, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15840476, 17905336, 22429796, 25417810, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004294710

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 8, 2023)

germline

clinical testing

PubMed (5)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing.

Tester DJ, Will ML, Haglund CM, Ackerman MJ.

Heart Rhythm. 2005 May;2(5):507-17.

PubMed [citation]

PMID:: 15840476

Long QT and Brugada syndrome gene mutations in New Zealand.

Chung SK, MacCormick JM, McCulley CH, Crawford J, Eddy CA, Mitchell EA, Shelling AN, French JK, Skinner JR, Rees MI.

Heart Rhythm. 2007 Oct;4(10):1306-14. Epub 2007 Jul 14.

PubMed [citation]

PMID:: 17905336

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004294710.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 774 of the KCNH2 protein (p.Asp774Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 15840476, 17905336, 22429796). ClinVar contains an entry for this variant (Variation ID: 67385). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 25417810). For these reasons, this variant has been classified as Pathogenic.

#	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

Last Updated: Sep 29, 2024

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