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NM_000238.4(KCNH2):c.2863C>G (p.Leu955Val)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(2);Uncertain significance(3)

Review status:
criteria provided, conflicting interpretations
Submissions:
7 (Most recent: Sep 25, 2021)
Last evaluated:
Oct 6, 2020
Accession:
VCV000067445.5
Variation ID:
67445
Description:
single nucleotide variant
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NM_000238.4(KCNH2):c.2863C>G (p.Leu955Val)

Allele ID
78341
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
7q36.1
Genomic location
7: 150947708 (GRCh38) GRCh38 UCSC
7: 150644796 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
LRG_288t1:c.2863C>G LRG_288p1:p.Leu955Val
NC_000007.13:g.150644796G>C
NM_000238.3:c.2863C>G NP_000229.1:p.Leu955Val missense
... more HGVS
Protein change
L615V, L955V
Other names
-
Canonical SPDI
NC_000007.14:150947707:G:C
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
The Genome Aggregation Database (gnomAD), exomes 0.00003
Exome Aggregation Consortium (ExAC) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Links
ClinGen: CA007537
dbSNP: rs199473012
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 1 criteria provided, single submitter Mar 21, 2020 RCV001185018.1
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Sep 4, 2019 RCV000413036.2
Conflicting interpretations of pathogenicity 3 criteria provided, conflicting interpretations Oct 6, 2020 RCV000509284.4
not provided 1 no assertion provided - RCV000058172.3

Clinical features observed in individuals with this variant

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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
KCNH2 Sufficient evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
2027 2098

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Likely pathogenic
(Mar 21, 2017)
criteria provided, single submitter
Method: clinical testing
None
Allele origin: germline
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute
Accession: SCV000748000.1
Submitted: (Aug 02, 2017)
Evidence details
Likely pathogenic
(Nov 06, 2017)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories
Accession: SCV000884047.1
Submitted: (Oct 10, 2018)
Evidence details
Uncertain significance
(Oct 06, 2020)
criteria provided, single submitter
Method: clinical testing
Long QT syndrome
Allele origin: germline
Invitae
Accession: SCV000828295.3
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (2)
Comment:
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 … (more)
Uncertain significance
(Sep 04, 2019)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000491005.1
Submitted: (Sep 25, 2021)
Evidence details
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported in ClinVar (ClinVar Variant ID# 67445; Landrum et al., 2016); … (more)
Uncertain significance
(Mar 21, 2020)
criteria provided, single submitter
Method: clinical testing
Arrhythmia
Allele origin: germline
Color Health, Inc
Accession: SCV001351142.1
Submitted: (May 19, 2020)
Comment:
This missense variant replaces leucine with valine at codon 955 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
Evidence details
not provided
(-)
no assertion provided
Method: literature only
Congenital long QT syndrome
Allele origin: germline
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000089692.3
Submitted: (Sep 22, 2016)
Evidence details
Publications
PubMed (2)
Comment:
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:18675227). This is a literature report, and does not necessarily … (more)
not provided
(-)
no assertion provided
Method: phenotyping only
Long QT syndrome
Allele origin: maternal
GenomeConnect, ClinGen
Accession: SCV000606894.1
Submitted: (Aug 22, 2017)
Evidence details
Comment:
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 … (more)

Functional evidence

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There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for this variant

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Title Author Journal Year Link
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
Paralogous annotation of disease-causing variants in long QT syndrome genes. Ware JS Human mutation 2012 PMID: 22581653
Cellular properties of C-terminal KCNH2 long QT syndrome mutations: description and divergence from clinical phenotypes. Biliczki P Heart rhythm 2008 PMID: 18675227

Text-mined citations for rs199473012...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 24, 2021