NM_000238.4(KCNH2):c.491G>A (p.Arg164His) AND Long QT syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 7, 2024
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:: RCV000473244.8

Allele description [Variation Report for NM_000238.4(KCNH2):c.491G>A (p.Arg164His)]

NM_000238.4(KCNH2):c.491G>A (p.Arg164His)

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.491G>A (p.Arg164His)

Other names:

NM_000238.3(KCNH2):c.491G>A(p.Arg164His); NM_172056.2(KCNH2):c.491G>A(p.Arg164His)

HGVS:

NC_000007.14:g.150958484C>T
NG_008916.1:g.24443G>A
NM_000238.4:c.491G>AMANE SELECT
NM_001406753.1:c.203G>A
NM_001406755.1:c.314G>A
NM_001406756.1:c.203G>A
NM_001406757.1:c.191G>A
NM_172056.3:c.491G>A
NP_000229.1:p.Arg164His
NP_000229.1:p.Arg164His
NP_001393682.1:p.Arg68His
NP_001393684.1:p.Arg105His
NP_001393685.1:p.Arg68His
NP_001393686.1:p.Arg64His
NP_742053.1:p.Arg164His
NP_742053.1:p.Arg164His
LRG_288t1:c.491G>A
LRG_288t2:c.491G>A
LRG_288:g.24443G>A
LRG_288p1:p.Arg164His
LRG_288p2:p.Arg164His
NC_000007.13:g.150655572C>T
NM_000238.3:c.491G>A
NM_172056.2:c.491G>A
NR_176254.1:n.899G>A
Q12809:p.Arg164His

Protein change:

R105H

Links:

UniProtKB: Q12809#VAR_074798; dbSNP: rs199472866

NCBI 1000 Genomes Browser:

rs199472866

Molecular consequence:

NM_000238.4:c.491G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.203G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.314G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.203G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.191G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.491G>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
SCV000543472	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 7, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19716085, 22429796, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000543472

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 7, 2024)

germline

clinical testing

PubMed (3)
[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

Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test.

Kapplinger JD, Tester DJ, Salisbury BA, Carr JL, Harris-Kerr C, Pollevick GD, Wilde AA, Ackerman MJ.

Heart Rhythm. 2009 Sep;6(9):1297-303. doi: 10.1016/j.hrthm.2009.05.021. Epub 2009 Jun 23.

PubMed [citation]

PMID:: 19716085
PMCID:: PMC3049907

End-recovery QTc: a useful metric for assessing genetic variants of unknown significance in long-QT syndrome.

Obeyesekere MN, Sy RW, Klein GJ, Gula LJ, Modi S, Conacher S, Leong-Sit P, Skanes AC, Yee R, Krahn AD.

J Cardiovasc Electrophysiol. 2012 Jun;23(6):637-42. doi: 10.1111/j.1540-8167.2011.02265.x. Epub 2012 Mar 19.

PubMed [citation]

PMID:: 22429796

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000543472.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 164 of the KCNH2 protein (p.Arg164His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with long QT syndrome (PMID: 19716085, 22429796; Invitae). ClinVar contains an entry for this variant (Variation ID: 67508). 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. 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

Last Updated: May 1, 2024

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