NM_000238.4(KCNH2):c.568G>A (p.Ala190Thr) AND Long QT syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 4, 2025
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:: RCV000532958.13

Allele description [Variation Report for NM_000238.4(KCNH2):c.568G>A (p.Ala190Thr)]

NM_000238.4(KCNH2):c.568G>A (p.Ala190Thr)

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.568G>A (p.Ala190Thr)

HGVS:

NC_000007.14:g.150958407C>T
NG_008916.1:g.24520G>A
NM_000238.4:c.568G>AMANE SELECT
NM_001406753.1:c.280G>A
NM_001406755.1:c.391G>A
NM_001406756.1:c.280G>A
NM_001406757.1:c.268G>A
NM_172056.3:c.568G>A
NP_000229.1:p.Ala190Thr
NP_000229.1:p.Ala190Thr
NP_001393682.1:p.Ala94Thr
NP_001393684.1:p.Ala131Thr
NP_001393685.1:p.Ala94Thr
NP_001393686.1:p.Ala90Thr
NP_742053.1:p.Ala190Thr
NP_742053.1:p.Ala190Thr
LRG_288t1:c.568G>A
LRG_288t2:c.568G>A
LRG_288:g.24520G>A
LRG_288p1:p.Ala190Thr
LRG_288p2:p.Ala190Thr
NC_000007.13:g.150655495C>T
NM_000238.3:c.568G>A
NM_172056.2:c.568G>A
NR_176254.1:n.976G>A

Protein change:

A131T

Links:

dbSNP: rs150817714

NCBI 1000 Genomes Browser:

rs150817714

Molecular consequence:

NM_000238.4:c.568G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.280G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.391G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.280G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.268G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.568G>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
SCV000627494	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 4, 2025)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29752375, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000627494

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 4, 2025)

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

Functional Invalidation of Putative Sudden Infant Death Syndrome-Associated Variants in the KCNH2-Encoded Kv11.1 Channel.

Smith JL, Tester DJ, Hall AR, Burgess DE, Hsu CC, Elayi SC, Anderson CL, January CT, Luo JZ, Hartzel DN, Mirshahi UL, Murray MF, Mirshahi T, Ackerman MJ, Delisle BP.

Circ Arrhythm Electrophysiol. 2018 May;11(5):e005859. doi: 10.1161/CIRCEP.117.005859.

PubMed [citation]

PMID:: 29752375
PMCID:: PMC11081002

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. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000627494.10

#	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 190 of the KCNH2 protein (p.Ala190Thr). 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 individual(s) with sudden infant death syndrome (PMID: 29752375). ClinVar contains an entry for this variant (Variation ID: 67512). 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 tolerated. 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 16, 2025

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