NM_000238.4(KCNH2):c.1909G>A (p.Glu637Lys) AND Long QT syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 10, 2018
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:: RCV000691309.8

Allele description [Variation Report for NM_000238.4(KCNH2):c.1909G>A (p.Glu637Lys)]

NM_000238.4(KCNH2):c.1909G>A (p.Glu637Lys)

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.1909G>A (p.Glu637Lys)

HGVS:

NC_000007.14:g.150951484C>T
NG_008916.1:g.31443G>A
NM_000238.4:c.1909G>AMANE SELECT
NM_001204798.2:c.889G>A
NM_001406753.1:c.1621G>A
NM_001406755.1:c.1732G>A
NM_001406756.1:c.1621G>A
NM_001406757.1:c.1609G>A
NM_172056.3:c.1909G>A
NM_172057.3:c.889G>A
NP_000229.1:p.Glu637Lys
NP_000229.1:p.Glu637Lys
NP_001191727.1:p.Glu297Lys
NP_001393682.1:p.Glu541Lys
NP_001393684.1:p.Glu578Lys
NP_001393685.1:p.Glu541Lys
NP_001393686.1:p.Glu537Lys
NP_742053.1:p.Glu637Lys
NP_742053.1:p.Glu637Lys
NP_742054.1:p.Glu297Lys
NP_742054.1:p.Glu297Lys
LRG_288t1:c.1909G>A
LRG_288t2:c.1909G>A
LRG_288t3:c.889G>A
LRG_288:g.31443G>A
LRG_288p1:p.Glu637Lys
LRG_288p2:p.Glu637Lys
LRG_288p3:p.Glu297Lys
NC_000007.13:g.150648572C>T
NM_000238.3:c.1909G>A
NM_172056.2:c.1909G>A
NM_172057.2:c.889G>A
NR_176254.1:n.2317G>A
NR_176255.1:n.1190G>A
Q12809:p.Glu637Lys

Protein change:

E297K

Links:

UniProtKB: Q12809#VAR_014379; dbSNP: rs199472968

NCBI 1000 Genomes Browser:

rs199472968

Molecular consequence:

NM_000238.4:c.1909G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001204798.2:c.889G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.1621G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.1732G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.1621G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.1609G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.1909G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.889G>A - 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
SCV000819084	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 10, 2018)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 12808265, 12062363, 23022675, 21109023, 21216356, 25417810, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000819084

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 10, 2018)

germline

clinical testing

PubMed (7)
[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

Q-T peak dispersion in congenital long QT syndrome: possible marker of mutation of HERG.

Inoue M, Shimizu M, Ino H, Yamaguchi M, Terai H, Hayashi K, Kiyama M, Sakata K, Hayashi T, Mabuchi H.

Circ J. 2003 Jun;67(6):495-8.

PubMed [citation]

PMID:: 12808265

Characterization of a novel missense mutation E637K in the pore-S6 loop of HERG in a patient with long QT syndrome.

Hayashi K, Shimizu M, Ino H, Yamaguchi M, Mabuchi H, Hoshi N, Higashida H.

Cardiovasc Res. 2002 Apr;54(1):67-76.

PubMed [citation]

PMID:: 12062363

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000819084.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces glutamic acid with lysine at codon 637 of the KCNH2 protein (p.Glu637Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with long QT syndrome (PMID: 12062363, 12808265). ClinVar contains an entry for this variant (Variation ID: 67329). Experimental studies have shown that this missense change disrupts protein trafficking, abolishing channel currents and causing dominant negative suppression of wild type channels (PMID: 12062363, 25417810, 23022675). A different missense substitution at this codon (p.Glu637Gly) has been determined to be pathogenic (PMID: 21109023, 21216356, 25417810). This suggests that the glutamic acid residue is critical for KCNH2 protein function and that other missense substitutions at this position may also be pathogenic. 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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