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NM_000238.4(KCNH2):c.1922C>A (p.Ser641Tyr) AND Long QT syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Apr 24, 2023
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:
RCV001924072.4

Allele description [Variation Report for NM_000238.4(KCNH2):c.1922C>A (p.Ser641Tyr)]

NM_000238.4(KCNH2):c.1922C>A (p.Ser641Tyr)

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.1922C>A (p.Ser641Tyr)
HGVS:
  • NC_000007.14:g.150951471G>T
  • NG_008916.1:g.31456C>A
  • NM_000238.4:c.1922C>AMANE SELECT
  • NM_001204798.2:c.902C>A
  • NM_001406753.1:c.1634C>A
  • NM_001406755.1:c.1745C>A
  • NM_001406756.1:c.1634C>A
  • NM_001406757.1:c.1622C>A
  • NM_172056.3:c.1922C>A
  • NM_172057.3:c.902C>A
  • NP_000229.1:p.Ser641Tyr
  • NP_000229.1:p.Ser641Tyr
  • NP_001191727.1:p.Ser301Tyr
  • NP_001393682.1:p.Ser545Tyr
  • NP_001393684.1:p.Ser582Tyr
  • NP_001393685.1:p.Ser545Tyr
  • NP_001393686.1:p.Ser541Tyr
  • NP_742053.1:p.Ser641Tyr
  • NP_742053.1:p.Ser641Tyr
  • NP_742054.1:p.Ser301Tyr
  • NP_742054.1:p.Ser301Tyr
  • LRG_288t1:c.1922C>A
  • LRG_288t2:c.1922C>A
  • LRG_288t3:c.902C>A
  • LRG_288:g.31456C>A
  • LRG_288p1:p.Ser641Tyr
  • LRG_288p2:p.Ser641Tyr
  • LRG_288p3:p.Ser301Tyr
  • NC_000007.13:g.150648559G>T
  • NM_000238.3:c.1922C>A
  • NM_172056.2:c.1922C>A
  • NM_172057.2:c.902C>A
  • NR_176254.1:n.2330C>A
  • NR_176255.1:n.1203C>A
Protein change:
S301Y
Links:
dbSNP: rs199472971
NCBI 1000 Genomes Browser:
rs199472971
Molecular consequence:
  • NM_000238.4:c.1922C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204798.2:c.902C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406753.1:c.1634C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406755.1:c.1745C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406756.1:c.1634C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406757.1:c.1622C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172056.3:c.1922C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172057.3:c.902C>A - 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
SCV002199424Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Apr 24, 2023) 		germlineclinical testing

PubMed (4)
[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

Mutation site dependent variability of cardiac events in Japanese LQT2 form of congenital long-QT syndrome.

Nagaoka I, Shimizu W, Itoh H, Yamamoto S, Sakaguchi T, Oka Y, Tsuji K, Ashihara T, Ito M, Yoshida H, Ohno S, Makiyama T, Miyamoto Y, Noda T, Kamakura S, Akao M, Horie M.

Circ J. 2008 May;72(5):694-9.

PubMed [citation]
PMID:
18441445

Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome.

Giudicessi JR, Kapplinger JD, Tester DJ, Alders M, Salisbury BA, Wilde AA, Ackerman MJ.

Circ Cardiovasc Genet. 2012 Oct 1;5(5):519-28. doi: 10.1161/CIRCGENETICS.112.963785. Epub 2012 Sep 4.

PubMed [citation]
PMID:
22949429
PMCID:
PMC3705705
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV002199424.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser641 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18441445, 22949429, 25417810; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1424837). This missense change has been observed in individual(s) with KCNH2-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 641 of the KCNH2 protein (p.Ser641Tyr).

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

Last Updated: Aug 11, 2024