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NM_000238.4(KCNH2):c.1262C>A (p.Thr421Lys) AND not provided

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 31, 2013
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:
RCV000181784.3

Allele description [Variation Report for NM_000238.4(KCNH2):c.1262C>A (p.Thr421Lys)]

NM_000238.4(KCNH2):c.1262C>A (p.Thr421Lys)

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.1262C>A (p.Thr421Lys)
Other names:
p.T421K:ACG>AAG
HGVS:
  • NC_000007.14:g.150952720G>T
  • NG_008916.1:g.30207C>A
  • NM_000238.4:c.1262C>AMANE SELECT
  • NM_001204798.2:c.242C>A
  • NM_001406753.1:c.974C>A
  • NM_001406755.1:c.1085C>A
  • NM_001406756.1:c.974C>A
  • NM_001406757.1:c.962C>A
  • NM_172056.3:c.1262C>A
  • NM_172057.3:c.242C>A
  • NP_000229.1:p.Thr421Lys
  • NP_000229.1:p.Thr421Lys
  • NP_001191727.1:p.Thr81Lys
  • NP_001393682.1:p.Thr325Lys
  • NP_001393684.1:p.Thr362Lys
  • NP_001393685.1:p.Thr325Lys
  • NP_001393686.1:p.Thr321Lys
  • NP_742053.1:p.Thr421Lys
  • NP_742053.1:p.Thr421Lys
  • NP_742054.1:p.Thr81Lys
  • NP_742054.1:p.Thr81Lys
  • LRG_288t1:c.1262C>A
  • LRG_288t2:c.1262C>A
  • LRG_288t3:c.242C>A
  • LRG_288:g.30207C>A
  • LRG_288p1:p.Thr421Lys
  • LRG_288p2:p.Thr421Lys
  • LRG_288p3:p.Thr81Lys
  • NC_000007.13:g.150649808G>T
  • NM_000238.2:c.1262C>A
  • NM_000238.3:c.1262C>A
  • NM_172056.2:c.1262C>A
  • NM_172057.2:c.242C>A
  • NR_176254.1:n.1670C>A
  • NR_176255.1:n.543C>A
Protein change:
T321K
Links:
dbSNP: rs199472894
NCBI 1000 Genomes Browser:
rs199472894
Molecular consequence:
  • NM_000238.4:c.1262C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204798.2:c.242C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406753.1:c.974C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406755.1:c.1085C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406756.1:c.974C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406757.1:c.962C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172056.3:c.1262C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172057.3:c.242C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: CN517202

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000234087GeneDx
criteria provided, single submitter

(GeneDx Variant Classification (06012015))		Pathogenic
(Mar 31, 2013) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

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

Details of each submission

From GeneDx, SCV000234087.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

p.Thr421Lys (ACG>AAG): c.1262 C>A in exon 6 of the KCNH2 (aka HERG) gene (NM_000238.2)While the Thr421Lys mutation in the KCNH2 gene has not been reported to our knowledge, a mutation affecting this same codon, Thr421Met, has been reported in association with LQTS (Tester D et al., 2005). Additionally, mutations in nearby residues (Leu413Pro, Tyr420Cys, Ala422Thr) have been reported in association with LQTS, further supporting the functional importance of this codon and this region of the protein. Thr421Lys results in a semi-conservative amino acid substitution of a neutral, polar Threonine with a positively charged Lysine at a position that is conserved across species. In silico analysis predicts Thr421Lys is probably damaging to the protein structure/function. Furthermore, Thr421Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, Thr421Lys in the KCNH2 gene is interpreted as a likely disease-causing mutation. The variant is found in LQT panel(s).

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

Last Updated: Nov 5, 2022