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NM_000238.4(KCNH2):c.1888G>A (p.Val630Ile)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(3);Uncertain significance(1)

Review status:
criteria provided, conflicting interpretations
Submissions:
4 (Most recent: Jul 14, 2021)
Last evaluated:
Oct 6, 2020
Accession:
VCV000222669.5
Variation ID:
222669
Description:
single nucleotide variant
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NM_000238.4(KCNH2):c.1888G>A (p.Val630Ile)

Allele ID
224342
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
7q36.1
Genomic location
7: 150951505 (GRCh38) GRCh38 UCSC
7: 150648593 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000007.13:g.150648593C>T
NC_000007.14:g.150951505C>T
NG_008916.1:g.31422G>A
... more HGVS
Protein change
V290I, V630I
Other names
-
Canonical SPDI
NC_000007.14:150951504:C:T
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00006
Links
ClinGen: CA029665
dbSNP: rs199472958
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Likely pathogenic 2 criteria provided, multiple submitters, no conflicts Sep 23, 2020 RCV000208259.2
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Oct 6, 2020 RCV000781487.3
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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
2038 2109

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Likely pathogenic
(Mar 23, 2015)
criteria provided, single submitter
Method: clinical testing
Long QT syndrome 2
Allele origin: germline
Blueprint Genetics
Accession: SCV000263978.2
Submitted: (Jan 15, 2016)
Evidence details
Likely pathogenic
(Oct 25, 2018)
criteria provided, single submitter
Method: clinical testing
Long QT syndrome
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919554.1
Submitted: (Apr 24, 2019)
Evidence details
Publications
PubMed (2)
Comment:
Variant summary: KCNH2 c.1888G>A (p.Val630Ile) results in a conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Four of … (more)
Uncertain significance
(Oct 06, 2020)
criteria provided, single submitter
Method: clinical testing
Long QT syndrome
Allele origin: germline
Invitae
Accession: SCV001400343.2
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (5)
Comment:
This sequence change replaces valine with isoleucine at codon 630 of the KCNH2 protein (p.Val630Ile). The valine residue is highly conserved and there is a … (more)
Likely pathogenic
(Sep 23, 2020)
criteria provided, single submitter
Method: clinical testing
Long QT syndrome 2
Allele origin: germline
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001754799.1
Submitted: (Jul 14, 2021)
Evidence details
Comment:
This c.1888G>A (p.Val630Ile) variant in the KCNH2 gene has been reported in two unrelated individuals affected with ventricular arrhythmias and sudden cardiac death (PMID: 30041777, … (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
Wearable cardioverter defibrillators for patients with long QT syndrome. Owen HJ International journal of cardiology 2018 PMID: 30041777
Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome. Lahrouchi N Journal of the American College of Cardiology 2017 PMID: 28449774
An in vivo cardiac assay to determine the functional consequences of putative long QT syndrome mutations. Jou CJ Circulation research 2013 PMID: 23303164
Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism. Anderson CL Circulation 2006 PMID: 16432067
Genomic structure of three long QT syndrome genes: KVLQT1, HERG, and KCNE1. Splawski I Genomics 1998 PMID: 9693036
Molecular determinants for activation and inactivation of HERG, a human inward rectifier potassium channel. Schönherr R The Journal of physiology 1996 PMID: 8799887

Text-mined citations for rs199472958...

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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 Dec 04, 2021