NM_000238.4(KCNH2):c.1342G>A (p.Ala448Thr) AND Long QT syndrome

Germline classification:: Uncertain significance (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:: RCV002559080.9

Allele description [Variation Report for NM_000238.4(KCNH2):c.1342G>A (p.Ala448Thr)]

NM_000238.4(KCNH2):c.1342G>A (p.Ala448Thr)

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.1342G>A (p.Ala448Thr)

HGVS:

NC_000007.14:g.150952640C>T
NG_008916.1:g.30287G>A
NM_000238.4:c.1342G>AMANE SELECT
NM_001204798.2:c.322G>A
NM_001406753.1:c.1054G>A
NM_001406755.1:c.1165G>A
NM_001406756.1:c.1054G>A
NM_001406757.1:c.1042G>A
NM_172056.3:c.1342G>A
NM_172057.3:c.322G>A
NP_000229.1:p.Ala448Thr
NP_000229.1:p.Ala448Thr
NP_001191727.1:p.Ala108Thr
NP_001393682.1:p.Ala352Thr
NP_001393684.1:p.Ala389Thr
NP_001393685.1:p.Ala352Thr
NP_001393686.1:p.Ala348Thr
NP_742053.1:p.Ala448Thr
NP_742053.1:p.Ala448Thr
NP_742054.1:p.Ala108Thr
NP_742054.1:p.Ala108Thr
LRG_288t1:c.1342G>A
LRG_288t2:c.1342G>A
LRG_288t3:c.322G>A
LRG_288:g.30287G>A
LRG_288p1:p.Ala448Thr
LRG_288p2:p.Ala448Thr
LRG_288p3:p.Ala108Thr
NC_000007.13:g.150649728C>T
NC_000007.13:g.150649728C>T
NM_000238.3:c.1342G>A
NM_172056.2:c.1342G>A
NM_172057.2:c.322G>A
NR_176254.1:n.1750G>A
NR_176255.1:n.623G>A

Protein change:

A108T

Links:

dbSNP: rs767723985

NCBI 1000 Genomes Browser:

rs767723985

Molecular consequence:

NM_000238.4:c.1342G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001204798.2:c.322G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.1054G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.1165G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.1054G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.1042G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.1342G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.322G>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
SCV003440625	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 27, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22727609, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003440625

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 27, 2023)

germline

clinical testing

PubMed (2)
[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

Clinical characteristics of 30 Czech families with long QT syndrome and KCNQ1 and KCNH2 gene mutations: importance of exercise testing.

Andrsova I, Novotny T, Kadlecova J, Bittnerova A, Vit P, Florianova A, Sisakova M, Gaillyova R, Manouskova L, Spinar J.

J Electrocardiol. 2012 Nov-Dec;45(6):746-51. doi: 10.1016/j.jelectrocard.2012.05.004. Epub 2012 Jun 22.

PubMed [citation]

PMID:: 22727609

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV003440625.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 448 of the KCNH2 protein (p.Ala448Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with personal and/or family history of long QT syndrome (PMID: 22727609). ClinVar contains an entry for this variant (Variation ID: 924051). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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: Apr 20, 2024

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