NM_000238.4(KCNH2):c.2660G>A (p.Arg887His) AND Long QT syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Feb 5, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000148534.18

Allele description [Variation Report for NM_000238.4(KCNH2):c.2660G>A (p.Arg887His)]

NM_000238.4(KCNH2):c.2660G>A (p.Arg887His)

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.2660G>A (p.Arg887His)

HGVS:

NC_000007.14:g.150948476C>T
NG_008916.1:g.34451G>A
NM_000238.4:c.2660G>AMANE SELECT
NM_172057.3:c.1640G>A
NP_000229.1:p.Arg887His
NP_000229.1:p.Arg887His
NP_742054.1:p.Arg547His
LRG_288t1:c.2660G>A
LRG_288:g.34451G>A
LRG_288p1:p.Arg887His
NC_000007.13:g.150645564C>T
NM_000238.2:c.2660G>A
NM_000238.3:c.2660G>A
Q12809:p.Arg887His

Protein change:

R547H

Links:

UniProtKB: Q12809#VAR_068281; dbSNP: rs199473432

NCBI 1000 Genomes Browser:

rs199473432

Molecular consequence:

NM_000238.4:c.2660G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_172057.3:c.1640G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Long QT syndrome (LQTS)
Identifiers:: MONDO: MONDO:0002442; MeSH: D008133; MedGen: C0023976

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SLC25A29 [Phascolarctos cinereus]
SLC25A29 [Phascolarctos cinereus]
Gene ID:110222369

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000190247	CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation	no assertion criteria provided	Uncertain significance (Jun 1, 2014)	germline	research
SCV000543460	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 19, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15840476, 26743238, 22653970, 28492532
SCV004841748	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Feb 5, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15840476, 22653970, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000190247

CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation

no assertion criteria provided

Uncertain significance
(Jun 1, 2014)

germline

research

SCV000543460

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 19, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004841748

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Feb 5, 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	9	not provided	not provided	108544	not provided	clinical testing, research

Citations

PubMed

Patient Outcomes From a Specialized Inherited Arrhythmia Clinic.

Adler A, Sadek MM, Chan AY, Dell E, Rutberg J, Davis D, Green MS, Spears DA, Gollob MH.

Circ Arrhythm Electrophysiol. 2016 Jan;9(1):e003440. doi: 10.1161/CIRCEP.115.003440.

PubMed [citation]

PMID:: 26743238

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

See all PubMed Citations (5)

Details of each submission

From CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190247.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000543460.8

#	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 arginine, which is basic and polar, with histidine, which is basic and polar, at codon 887 of the KCNH2 protein (p.Arg887His). 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 clinical features of KCNH2-related conditions (PMID: 15840476, 26743238). ClinVar contains an entry for this variant (Variation ID: 67423). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects KCNH2 function (PMID: 22653970). 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

From All of Us Research Program, National Institutes of Health, SCV004841748.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	9	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces arginine with histidine at codon 887 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental study has shown that this variant may inhibit PKC-dependent phosphorylation and ultimately inhibit cell surface expression and function of the potassium channel (PMID: 22653970). This variant has been reported in an individual affected with arrhythmia (PMID 26743238) and in an individual referred for long QT genetic testing (PMID: 15840476). This variant has been identified in 2/248800 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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	108544	not provided	not provided		9	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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