NM_000238.4(KCNH2):c.1853C>T (p.Thr618Ile) AND Long QT syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 27, 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:: RCV001376739.6

Allele description [Variation Report for NM_000238.4(KCNH2):c.1853C>T (p.Thr618Ile)]

NM_000238.4(KCNH2):c.1853C>T (p.Thr618Ile)

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.1853C>T (p.Thr618Ile)

HGVS:

NC_000007.14:g.150951540G>A
NG_008916.1:g.31387C>T
NM_000238.4:c.1853C>TMANE SELECT
NM_001204798.2:c.833C>T
NM_001406753.1:c.1565C>T
NM_001406755.1:c.1676C>T
NM_001406756.1:c.1565C>T
NM_001406757.1:c.1553C>T
NM_172056.3:c.1853C>T
NM_172057.3:c.833C>T
NP_000229.1:p.Thr618Ile
NP_000229.1:p.Thr618Ile
NP_001191727.1:p.Thr278Ile
NP_001393682.1:p.Thr522Ile
NP_001393684.1:p.Thr559Ile
NP_001393685.1:p.Thr522Ile
NP_001393686.1:p.Thr518Ile
NP_742053.1:p.Thr618Ile
NP_742053.1:p.Thr618Ile
NP_742054.1:p.Thr278Ile
NP_742054.1:p.Thr278Ile
LRG_288t1:c.1853C>T
LRG_288t2:c.1853C>T
LRG_288t3:c.833C>T
LRG_288:g.31387C>T
LRG_288p1:p.Thr618Ile
LRG_288p2:p.Thr618Ile
LRG_288p3:p.Thr278Ile
NC_000007.13:g.150648628G>A
NM_000238.3:c.1853C>T
NM_172056.2:c.1853C>T
NM_172057.2:c.833C>T
NR_176254.1:n.2261C>T
NR_176255.1:n.1134C>T

Protein change:

T278I

Links:

dbSNP: rs199472947

NCBI 1000 Genomes Browser:

rs199472947

Molecular consequence:

NM_000238.4:c.1853C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001204798.2:c.833C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.1565C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.1676C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.1565C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.1553C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.1853C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.833C>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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Homo sapiens mRNA for cardiac potassium channel subunit (Kv6.2)
Homo sapiens mRNA for cardiac potassium channel subunit (Kv6.2)
gi|6006492|emb|AJ011021.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001573900	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 27, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21130771, 23300672, 23471968, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001573900

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 27, 2023)

germline

clinical testing

PubMed (4)
[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

A novel mutation in the KCNH2 gene associated with short QT syndrome.

Sun Y, Quan XQ, Fromme S, Cox RH, Zhang P, Zhang L, Guo D, Guo J, Patel C, Kowey PR, Yan GX.

J Mol Cell Cardiol. 2011 Mar;50(3):433-41. doi: 10.1016/j.yjmcc.2010.11.017. Epub 2010 Dec 3.

PubMed [citation]

PMID:: 21130771

Action potential clamp and pharmacology of the variant 1 Short QT Syndrome T618I hERG K⁺ channel.

El Harchi A, Melgari D, Zhang YH, Zhang H, Hancox JC.

PLoS One. 2012;7(12):e52451. doi: 10.1371/journal.pone.0052451. Epub 2012 Dec 26.

PubMed [citation]

PMID:: 23300672
PMCID:: PMC3530446

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001573900.4

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

Description

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 618 of the KCNH2 protein (p.Thr618Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with short QT syndrome (PMID: 21130771; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67297). 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: 21130771, 23300672, 23471968). 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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