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NM_005477.3(HCN4):c.458A>G (p.Glu153Gly)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely benign(3);Uncertain significance(2)

Review status:
criteria provided, conflicting interpretations
Submissions:
6 (Most recent: Jun 12, 2019)
Last evaluated:
Jun 11, 2019
Accession:
VCV000180370.4
Variation ID:
180370
Description:
single nucleotide variant
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NM_005477.3(HCN4):c.458A>G (p.Glu153Gly)

Allele ID
178709
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
15q24.1
Genomic location
15: 73367813 (GRCh38) GRCh38 UCSC
15: 73660154 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000015.10:g.73367813T>C
NC_000015.9:g.73660154T>C
NM_005477.3:c.458A>G NP_005468.1:p.Glu153Gly missense
NG_009063.1:g.6452A>G
Protein change
E153G
Other names
-
Functional consequence
-
Global minor allele frequency (GMAF)
0.00020 (C)

Allele frequency
Exome Aggregation Consortium (ExAC) 0.00000
1000 Genomes Project 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00145
The Genome Aggregation Database (gnomAD) 0.00105
The Genome Aggregation Database (gnomAD), exomes 0.00206
Links
ClinGen: CA238824
dbSNP: rs560874115
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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 Feb 6, 2017 RCV000255885.4
Likely benign 1 criteria provided, single submitter Apr 19, 2017 RCV000618430.1
Likely benign 1 criteria provided, single submitter Jun 11, 2019 RCV000852712.1
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Mar 5, 2019 RCV000723946.2
Uncertain significance 1 no assertion criteria provided Oct 28, 2014 RCV000157245.1
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
HCN4 - - GRCh38
GRCh37
437 467

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Feb 06, 2017)
criteria provided, single submitter
Method: clinical testing
not specified
Allele origin: germline
GeneDx
Accession: SCV000321764.5
Submitted: (Jul 13, 2017)
Evidence details
Comment:
The E153G variant of uncertain significance in the HCN4 gene has not been published as a pathogenic variant or beenreported as a benign variant to ... (more)
Likely benign
(Apr 19, 2017)
criteria provided, single submitter
Method: clinical testing
cardiovascular phenotype
Allele origin: germline
Ambry Genetics
Accession: SCV000735071.2
Submitted: (Jul 30, 2018)
Evidence details
Publications
PubMed (3)
Comment:
Lines of evidence used in support of classification: In silico models in agreement (benign),Does not segregate with disease in family study (genes with incomplete penetrance)
Likely benign
(Mar 05, 2019)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Invitae
Accession: SCV000288913.5
Submitted: (Mar 14, 2019)
Evidence details
Uncertain significance
(Sep 13, 2018)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics
Accession: SCV000224482.5
Submitted: (Sep 19, 2018)
Evidence details
Other databases
http://www.egl-eurofins.com/em...
Likely benign
(Jun 11, 2019)
criteria provided, single submitter
Method: clinical testing
Dilated cardiomyopathy
Cardiomyopathy
Allele origin: germline
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego
Accession: SCV000995426.1
Submitted: (Jun 12, 2019)
Evidence details
Uncertain significance
(Oct 28, 2014)
no assertion criteria provided
Method: clinical testing
Brugada syndrome
Allele origin: germline
Blueprint Genetics
Accession: SCV000206972.1
Submitted: (Feb 02, 2015)
Evidence details

Citations for this variant

Title Author Journal Year Link
Targeted Next-Generation Sequencing of 51 Genes Involved in Primary Electrical Disease. Proost D The Journal of molecular diagnostics : JMD 2017 PMID: 28341588
A Distinct Cardiomyopathy: HCN4 Syndrome Comprising Myocardial Noncompaction, Bradycardia, Mitral Valve Defects, and Aortic Dilation. Schweizer PA Journal of the American College of Cardiology 2017 PMID: 28254188
A novel trafficking-defective HCN4 mutation is associated with early-onset atrial fibrillation. Macri V Heart rhythm 2014 PMID: 24607718
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HCN4 - - - -

Record last updated Dec 17, 2019