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NM_000238.4(KCNH2):c.1837A>G (p.Thr613Ala) AND Long QT syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jan 21, 2024
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:
RCV002914134.3

Allele description [Variation Report for NM_000238.4(KCNH2):c.1837A>G (p.Thr613Ala)]

NM_000238.4(KCNH2):c.1837A>G (p.Thr613Ala)

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.1837A>G (p.Thr613Ala)
HGVS:
  • NC_000007.14:g.150951556T>C
  • NG_008916.1:g.31371A>G
  • NM_000238.4:c.1837A>GMANE SELECT
  • NM_001204798.2:c.817A>G
  • NM_001406753.1:c.1549A>G
  • NM_001406755.1:c.1660A>G
  • NM_001406756.1:c.1549A>G
  • NM_001406757.1:c.1537A>G
  • NM_172056.3:c.1837A>G
  • NM_172057.3:c.817A>G
  • NP_000229.1:p.Thr613Ala
  • NP_000229.1:p.Thr613Ala
  • NP_001191727.1:p.Thr273Ala
  • NP_001393682.1:p.Thr517Ala
  • NP_001393684.1:p.Thr554Ala
  • NP_001393685.1:p.Thr517Ala
  • NP_001393686.1:p.Thr513Ala
  • NP_742053.1:p.Thr613Ala
  • NP_742053.1:p.Thr613Ala
  • NP_742054.1:p.Thr273Ala
  • NP_742054.1:p.Thr273Ala
  • LRG_288t1:c.1837A>G
  • LRG_288t2:c.1837A>G
  • LRG_288t3:c.817A>G
  • LRG_288:g.31371A>G
  • LRG_288p1:p.Thr613Ala
  • LRG_288p2:p.Thr613Ala
  • LRG_288p3:p.Thr273Ala
  • NC_000007.13:g.150648644T>C
  • NM_000238.3:c.1837A>G
  • NM_172056.2:c.1837A>G
  • NM_172057.2:c.817A>G
  • NR_176254.1:n.2245A>G
  • NR_176255.1:n.1118A>G
Protein change:
T273A
Molecular consequence:
  • NM_000238.4:c.1837A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204798.2:c.817A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406753.1:c.1549A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406755.1:c.1660A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406756.1:c.1549A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406757.1:c.1537A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172056.3:c.1837A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172057.3:c.817A>G - 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
SCV003258431Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Jan 21, 2024) 		germlineclinical testing

PubMed (8)
[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

The Mutation P.T613a in the Pore Helix of the Kv 11.1 Potassium Channel is Associated with Long QT Syndrome.

Poulsen KL, Hotait M, Calloe K, Klaerke DA, Rebeiz A, Nemer G, Tejada MA, Refaat MM.

Pacing Clin Electrophysiol. 2015 Nov;38(11):1304-9. doi: 10.1111/pace.12693. Epub 2015 Aug 7.

PubMed [citation]
PMID:
26173150

Novel KCNQ1 and HERG missense mutations in Dutch long-QT families.

Jongbloed RJ, Wilde AA, Geelen JL, Doevendans P, Schaap C, Van Langen I, van Tintelen JP, Cobben JM, Beaufort-Krol GC, Geraedts JP, Smeets HJ.

Hum Mutat. 1999;13(4):301-10.

PubMed [citation]
PMID:
10220144
See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003258431.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 613 of the KCNH2 protein (p.Thr613Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 26173150). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2049671). 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. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 26173150). This variant disrupts the p.Thr613 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10220144, 10862094, 10973849, 11524404, 14720170, 25417810). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Sep 29, 2024