NM_000238.3(KCNH2):c.2863C>G (p.Leu955Val) AND Long QT syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Oct 6, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000509284.4

Allele description [Variation Report for NM_000238.3(KCNH2):c.2863C>G (p.Leu955Val)]

NM_000238.3(KCNH2):c.2863C>G (p.Leu955Val)

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_000238.3(KCNH2):c.2863C>G (p.Leu955Val)
HGVS:
  • NC_000007.14:g.150947708G>C
  • NG_008916.1:g.35219C>G
  • NM_000238.3:c.2863C>G
  • NM_172057.2:c.1843C>G
  • NP_000229.1:p.Leu955Val
  • NP_742054.1:p.Leu615Val
  • LRG_288t1:c.2863C>G
  • LRG_288t3:c.1843C>G
  • LRG_288:g.35219C>G
  • LRG_288p1:p.Leu955Val
  • LRG_288p3:p.Leu615Val
  • NC_000007.13:g.150644796G>C
  • NM_000238.2:c.2863C>G
Protein change:
L615V
Links:
dbSNP: rs199473012
NCBI 1000 Genomes Browser:
rs199473012
Molecular consequence:
  • NM_000238.3:c.2863C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_172057.2:c.1843C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Long QT syndrome (LQTS)
Identifiers:
MONDO: MONDO:0002442; MeSH: D008133; MedGen: C0023976; OMIM: PS192500

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000606894GenomeConnect, ClinGenno assertion providednot providedmaternalphenotyping only

SCV000748000Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institutecriteria provided, single submitter
Likely pathogenic
(Mar 21, 2017)
germlineclinical testing

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

SCV000828295Invitaecriteria provided, single submitter
Uncertain significance
(Oct 6, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedmaternalunknownnot providednot providednot providednot providednot providedphenotyping only
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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

Cellular properties of C-terminal KCNH2 long QT syndrome mutations: description and divergence from clinical phenotypes.

Biliczki P, Girmatsion Z, Harenkamp S, Anneken L, Brandes RP, Varro A, Marschall C, Herrera D, Hohnloser SH, Nattel S, Ehrlich JR.

Heart Rhythm. 2008 Aug;5(8):1159-67. doi: 10.1016/j.hrthm.2008.04.016. Epub 2008 Apr 22.

PubMed [citation]
PMID:
18675227
See all PubMed Citations (3)

Details of each submission

From GenomeConnect, ClinGen, SCV000606894.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedphenotyping onlynot provided

Description

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1maternalunknownnot providednot providedvalidationnot providednot providednot providednot provided

From Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute, SCV000748000.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000828295.3

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

Description

This sequence change replaces leucine with valine at codon 955 of the KCNH2 protein (p.Leu955Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs199473012, ExAC 0.01%). This variant has been observed in an individual affected with long QT syndrome (PMID: 18675227). ClinVar contains an entry for this variant (Variation ID: 67445). Experimental studies have shown that this missense change causes a trafficking deficiency, potential aggregate formation and decreased function of the ion channel (PMID: 18675227). 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: Oct 7, 2021

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