NM_000238.4(KCNH2):c.1067G>A (p.Arg356His) AND Long QT syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 27, 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:: RCV000157263.17

Allele description [Variation Report for NM_000238.4(KCNH2):c.1067G>A (p.Arg356His)]

NM_000238.4(KCNH2):c.1067G>A (p.Arg356His)

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.1067G>A (p.Arg356His)

HGVS:

NC_000007.14:g.150957352C>T
NG_008916.1:g.25575G>A
NM_000238.4:c.1067G>AMANE SELECT
NM_001406753.1:c.779G>A
NM_001406755.1:c.890G>A
NM_001406756.1:c.779G>A
NM_001406757.1:c.767G>A
NM_172056.3:c.1067G>A
NP_000229.1:p.Arg356His
NP_000229.1:p.Arg356His
NP_001393682.1:p.Arg260His
NP_001393684.1:p.Arg297His
NP_001393685.1:p.Arg260His
NP_001393686.1:p.Arg256His
NP_742053.1:p.Arg356His
NP_742053.1:p.Arg356His
LRG_288t1:c.1067G>A
LRG_288t2:c.1067G>A
LRG_288:g.25575G>A
LRG_288p1:p.Arg356His
LRG_288p2:p.Arg356His
NC_000007.13:g.150654440C>T
NM_000238.2:c.1067G>A
NM_000238.3:c.1067G>A
NM_172056.2:c.1067G>A
NR_176254.1:n.1475G>A

Protein change:

R256H

Links:

dbSNP: rs730880118

NCBI 1000 Genomes Browser:

rs730880118

Molecular consequence:

NM_000238.4:c.1067G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406753.1:c.779G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406755.1:c.890G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406756.1:c.779G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406757.1:c.767G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_172056.3:c.1067G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000206993	Blueprint Genetics	no assertion criteria provided	Uncertain significance (May 28, 2014)	germline	clinical testing
SCV000543444	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 27, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24667783, 28492532
SCV004844030	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 13, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24667783, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000206993

Blueprint Genetics

no assertion criteria provided

Uncertain significance
(May 28, 2014)

germline

clinical testing

SCV000543444

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 27, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004844030

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 13, 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	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	16	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

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

Genetic analysis, in silico prediction, and family segregation in long QT syndrome.

Riuró H, Campuzano O, Berne P, Arbelo E, Iglesias A, Pérez-Serra A, Coll-Vidal M, Partemi S, Mademont-Soler I, Picó F, Allegue C, Oliva A, Gerstenfeld E, Sarquella-Brugada G, Castro-Urda V, Fernández-Lozano I, Mont L, Brugada J, Scornik FS, Brugada R.

Eur J Hum Genet. 2015 Jan;23(1):79-85. doi: 10.1038/ejhg.2014.54. Epub 2014 Mar 26.

PubMed [citation]

PMID:: 24667783
PMCID:: PMC4266740

See all PubMed Citations (3)

Details of each submission

From Blueprint Genetics, SCV000206993.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Invitae, SCV000543444.9

#	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 arginine, which is basic and polar, with histidine, which is basic and polar, at codon 356 of the KCNH2 protein (p.Arg356His). This variant is present in population databases (rs730880118, gnomAD 0.01%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 24667783). ClinVar contains an entry for this variant (Variation ID: 180382). 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

From All of Us Research Program, National Institutes of Health, SCV004844030.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	16	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces arginine with histidine at codon 356 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with long QT syndrome (PMID: 24667783). This variant has been identified in 15/277414 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		16	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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