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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:
RCV000157263.19

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:
17

Condition(s)

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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000206993Blueprint Genetics
no assertion criteria provided
Uncertain significance
(May 28, 2014) 		germlineclinical testing

SCV000543444Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jan 27, 2024) 		germlineclinical testing

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

SCV004844030All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Dec 13, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown16not providednot provided108544not providedclinical testing
not providedgermlineyes1not providednot providednot providednot providedclinical 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. doi: 10.1038/s41436-019-0624-9.

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000543444.9

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided16not providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided16not providednot providednot provided

Last Updated: Nov 3, 2024