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NM_000238.4(KCNH2):c.1904A>C (p.Asn635Thr) AND Long QT syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Apr 9, 2022
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:
RCV003055250.3

Allele description [Variation Report for NM_000238.4(KCNH2):c.1904A>C (p.Asn635Thr)]

NM_000238.4(KCNH2):c.1904A>C (p.Asn635Thr)

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.1904A>C (p.Asn635Thr)
HGVS:
  • NC_000007.14:g.150951489T>G
  • NG_008916.1:g.31438A>C
  • NM_000238.4:c.1904A>CMANE SELECT
  • NM_001204798.2:c.884A>C
  • NM_001406753.1:c.1616A>C
  • NM_001406755.1:c.1727A>C
  • NM_001406756.1:c.1616A>C
  • NM_001406757.1:c.1604A>C
  • NM_172056.3:c.1904A>C
  • NM_172057.3:c.884A>C
  • NP_000229.1:p.Asn635Thr
  • NP_000229.1:p.Asn635Thr
  • NP_001191727.1:p.Asn295Thr
  • NP_001393682.1:p.Asn539Thr
  • NP_001393684.1:p.Asn576Thr
  • NP_001393685.1:p.Asn539Thr
  • NP_001393686.1:p.Asn535Thr
  • NP_742053.1:p.Asn635Thr
  • NP_742053.1:p.Asn635Thr
  • NP_742054.1:p.Asn295Thr
  • NP_742054.1:p.Asn295Thr
  • LRG_288t1:c.1904A>C
  • LRG_288t2:c.1904A>C
  • LRG_288t3:c.884A>C
  • LRG_288:g.31438A>C
  • LRG_288p1:p.Asn635Thr
  • LRG_288p2:p.Asn635Thr
  • LRG_288p3:p.Asn295Thr
  • NC_000007.13:g.150648577T>G
  • NM_000238.3:c.1904A>C
  • NM_172056.2:c.1904A>C
  • NM_172057.2:c.884A>C
  • NR_176254.1:n.2312A>C
  • NR_176255.1:n.1185A>C
Protein change:
N295T
Molecular consequence:
  • NM_000238.4:c.1904A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204798.2:c.884A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406753.1:c.1616A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406755.1:c.1727A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406756.1:c.1616A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406757.1:c.1604A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172056.3:c.1904A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172057.3:c.884A>C - 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
SCV003342218Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Apr 9, 2022) 		germlineclinical testing

PubMed (2)
[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

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

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003342218.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 635 of the KCNH2 protein (p.Asn635Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of long QT syndrome (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Asn635 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been observed in individuals with KCNH2-related conditions (PMID: 22949429; Invitae), which suggests that this may be a clinically significant amino acid residue. 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

Last Updated: Sep 29, 2024