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NM_000238.4(KCNH2):c.1864C>T (p.Leu622Phe) AND Long QT syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Mar 12, 2017
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:
RCV000552720.6

Allele description [Variation Report for NM_000238.4(KCNH2):c.1864C>T (p.Leu622Phe)]

NM_000238.4(KCNH2):c.1864C>T (p.Leu622Phe)

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.1864C>T (p.Leu622Phe)
HGVS:
  • NC_000007.14:g.150951529G>A
  • NG_008916.1:g.31398C>T
  • NM_000238.4:c.1864C>TMANE SELECT
  • NM_001204798.2:c.844C>T
  • NM_001406753.1:c.1576C>T
  • NM_001406755.1:c.1687C>T
  • NM_001406756.1:c.1576C>T
  • NM_001406757.1:c.1564C>T
  • NM_172056.3:c.1864C>T
  • NM_172057.3:c.844C>T
  • NP_000229.1:p.Leu622Phe
  • NP_000229.1:p.Leu622Phe
  • NP_001191727.1:p.Leu282Phe
  • NP_001393682.1:p.Leu526Phe
  • NP_001393684.1:p.Leu563Phe
  • NP_001393685.1:p.Leu526Phe
  • NP_001393686.1:p.Leu522Phe
  • NP_742053.1:p.Leu622Phe
  • NP_742053.1:p.Leu622Phe
  • NP_742054.1:p.Leu282Phe
  • NP_742054.1:p.Leu282Phe
  • LRG_288t1:c.1864C>T
  • LRG_288t2:c.1864C>T
  • LRG_288t3:c.844C>T
  • LRG_288:g.31398C>T
  • LRG_288p1:p.Leu622Phe
  • LRG_288p2:p.Leu622Phe
  • LRG_288p3:p.Leu282Phe
  • NC_000007.13:g.150648617G>A
  • NM_000238.3:c.1864C>T
  • NM_172056.2:c.1864C>T
  • NM_172057.2:c.844C>T
  • NR_176254.1:n.2272C>T
  • NR_176255.1:n.1145C>T
  • Q12809:p.Leu622Phe
Protein change:
L282F
Links:
UniProtKB: Q12809#VAR_068268; dbSNP: rs199473525
NCBI 1000 Genomes Browser:
rs199473525
Molecular consequence:
  • NM_000238.4:c.1864C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204798.2:c.844C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406753.1:c.1576C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406755.1:c.1687C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406756.1:c.1576C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406757.1:c.1564C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172056.3:c.1864C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172057.3:c.844C>T - 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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000627444Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Mar 12, 2017) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Pore helices play a dynamic role as integrators of domain motion during Kv11.1 channel inactivation gating.

Perry MD, Ng CA, Vandenberg JI.

J Biol Chem. 2013 Apr 19;288(16):11482-91. doi: 10.1074/jbc.M113.461442. Epub 2013 Mar 7.

PubMed [citation]
PMID:
23471968
PMCID:
PMC3630859

Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction.

Itoh H, Berthet M, Fressart V, Denjoy I, Maugenre S, Klug D, Mizusawa Y, Makiyama T, Hofman N, Stallmeyer B, Zumhagen S, Shimizu W, Wilde AA, Schulze-Bahr E, Horie M, Tezenas du Montcel S, Guicheney P.

Eur J Hum Genet. 2016 Aug;24(8):1160-6. doi: 10.1038/ejhg.2015.257. Epub 2015 Dec 16.

PubMed [citation]
PMID:
26669661
PMCID:
PMC4970673
See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000627444.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change alters the expression or potassium selectivity of in vitro expressed KCNH2, though the clinical significance of this observation is uncertain (PMID: 23471968). This variant has been reported in an individual affected with long QT syndrome (PMID: 26669661) and in an individual with a clinical suspicion of long QT syndrome (PMID: 15840476). ClinVar contains an entry for this variant (Variation ID: 67301). This variant is not present in population databases (rs199473525, ExAC no frequency). This variant identified in the KCNH2 gene is located in the pore region of the resulting protein (PMID: 19841300, 25348405). For more information about the location of this variant, please visit www.invitae.com/KCNH2-topology. This sequence change replaces leucine with phenylalanine at codon 622 of the KCNH2 protein (p.Leu622Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine.

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

Last Updated: Sep 29, 2024