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NM_000238.4(KCNH2):c.2053C>T (p.Arg685Cys) AND Long QT syndrome

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Aug 28, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000631573.16

Allele description

NM_000238.4(KCNH2):c.2053C>T (p.Arg685Cys)

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.2053C>T (p.Arg685Cys)
HGVS:
  • NC_000007.14:g.150951013G>A
  • NG_008916.1:g.31914C>T
  • NM_000238.4:c.2053C>TMANE SELECT
  • NM_001204798.2:c.1033C>T
  • NM_001406753.1:c.1765C>T
  • NM_001406755.1:c.1876C>T
  • NM_001406756.1:c.1765C>T
  • NM_001406757.1:c.1753C>T
  • NM_172056.3:c.2053C>T
  • NM_172057.3:c.1033C>T
  • NP_000229.1:p.Arg685Cys
  • NP_000229.1:p.Arg685Cys
  • NP_001191727.1:p.Arg345Cys
  • NP_001393682.1:p.Arg589Cys
  • NP_001393684.1:p.Arg626Cys
  • NP_001393685.1:p.Arg589Cys
  • NP_001393686.1:p.Arg585Cys
  • NP_742053.1:p.Arg685Cys
  • NP_742053.1:p.Arg685Cys
  • NP_742054.1:p.Arg345Cys
  • NP_742054.1:p.Arg345Cys
  • LRG_288t1:c.2053C>T
  • LRG_288t2:c.2053C>T
  • LRG_288t3:c.1033C>T
  • LRG_288:g.31914C>T
  • LRG_288p1:p.Arg685Cys
  • LRG_288p2:p.Arg685Cys
  • LRG_288p3:p.Arg345Cys
  • NC_000007.13:g.150648101G>A
  • NM_000238.3:c.2053C>T
  • NM_172056.2:c.2053C>T
  • NM_172057.2:c.1033C>T
  • NR_176254.1:n.2461C>T
  • NR_176255.1:n.1334C>T
Protein change:
R345C
Links:
dbSNP: rs778135438
NCBI 1000 Genomes Browser:
rs778135438
Molecular consequence:
  • NM_000238.4:c.2053C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001204798.2:c.1033C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406753.1:c.1765C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406755.1:c.1876C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406756.1:c.1765C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406757.1:c.1753C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172056.3:c.2053C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172057.3:c.1033C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
2

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
SCV000752655Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Mar 9, 2023) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004828280All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Aug 28, 2023) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown2not providednot provided108544not providedclinical testing

Citations

PubMed

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Invitae, SCV000752655.4

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

Description

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. 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. ClinVar contains an entry for this variant (Variation ID: 448974). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 685 of the KCNH2 protein (p.Arg685Cys).

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

From All of Us Research Program, National Institutes of Health, SCV004828280.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (1)

Description

This missense variant replaces arginine with cysteine at codon 685 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with KCNH2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided2not providednot providednot provided

Last Updated: Sep 16, 2024