HCN4: BS1, BS2
ClinVar Genomic variation as it relates to human health
NM_005477.3(HCN4):c.2648C>G (p.Pro883Arg)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(20)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Benign/Likely benign
20
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_005477.3(HCN4):c.2648C>G (p.Pro883Arg)
Variation ID: 137542 Accession: VCV000137542.45
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q24.1 15: 73323445 (GRCh38) [ NCBI UCSC ] 15: 73615786 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 4, 2015 Oct 20, 2024 Jul 1, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_005477.3:c.2648C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005468.1:p.Pro883Arg missense NC_000015.10:g.73323445G>C NC_000015.9:g.73615786G>C NG_009063.1:g.50820C>G - Protein change
- P883R
- Other names
-
p.P883R:CCC>CGC
- Canonical SPDI
- NC_000015.10:73323444:G:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00339 (C)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 0.00339
1000 Genomes Project 30x 0.00359
The Genome Aggregation Database (gnomAD) 0.00737
Trans-Omics for Precision Medicine (TOPMed) 0.00752
The Genome Aggregation Database (gnomAD), exomes 0.00775
Exome Aggregation Consortium (ExAC) 0.00877
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00976
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| HCN4 | - | - |
GRCh38 GRCh37 |
1589 | 1772 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Benign/Likely benign (6) |
criteria provided, multiple submitters, no conflicts
|
Apr 10, 2023 | RCV000125353.17 | |
| Benign (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2024 | RCV000232306.15 | |
| Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 1, 2017 | RCV000578029.5 | |
| Benign (1) |
criteria provided, single submitter
|
Nov 24, 2015 | RCV000620859.3 | |
| Benign (1) |
criteria provided, single submitter
|
Aug 1, 2017 | RCV000577973.1 | |
| Benign/Likely benign (6) |
criteria provided, multiple submitters, no conflicts
|
Jul 1, 2024 | RCV000711887.22 | |
| Benign (1) |
criteria provided, single submitter
|
Apr 17, 2019 | RCV000852708.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
|
Benign
(Sep 20, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000842298.1
First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018 |
|
|
|
Likely benign
(Apr 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003928225.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
|
|
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Benign
(Oct 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV003799833.3
First in ClinVar: Feb 13, 2023 Last updated: Feb 20, 2024 |
|
|
|
Likely benign
(-)
|
criteria provided, single submitter
Method: not provided
|
not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005211020.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
|
|
|
Benign
(Jul 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004132794.10
First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024 |
Comment:
HCN4: BS1, BS2
Number of individuals with the variant: 4
|
|
|
Benign
(Jun 24, 2013)
|
criteria provided, single submitter
Method: research
|
not specified
Affected status: unknown
Allele origin:
unknown
|
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000050819.1 First in ClinVar: Jun 04, 2015 Last updated: Jun 04, 2015
Comments (2):
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for details. (less)
Medical sequencing
|
Number of individuals with the variant: 7
|
|
|
Benign
(Aug 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Brugada syndrome 8
Affected status: unknown
Allele origin:
germline
|
Phosphorus, Inc.
Accession: SCV000679911.1
First in ClinVar: Jan 27, 2018 Last updated: Jan 27, 2018 |
Number of individuals with the variant: 1
|
|
|
Benign
(Aug 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Sick sinus syndrome 2, autosomal dominant
Affected status: unknown
Allele origin:
germline
|
Phosphorus, Inc.
Accession: SCV000679913.1
First in ClinVar: Jan 28, 2018 Last updated: Jan 28, 2018 |
Number of individuals with the variant: 1
|
|
|
Benign
(Aug 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Left ventricular noncompaction
Affected status: unknown
Allele origin:
germline
|
Phosphorus, Inc.
Accession: SCV000679912.1
First in ClinVar: Jan 28, 2018 Last updated: Jan 28, 2018 |
Number of individuals with the variant: 1
|
|
|
Benign
(May 24, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000341478.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 2
Sex: mixed
|
|
|
Benign
(Apr 17, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Atrial fibrillation
Hypertrophic cardiomyopathy Cardiomyopathy Ventricular tachycardia
Affected status: yes
Allele origin:
germline
|
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego
Accession: SCV000995422.1
First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019 |
Number of individuals with the variant: 6
|
|
|
Benign
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Brugada syndrome 8
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001139653.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Likely benign
(Apr 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Sick sinus syndrome 2, autosomal dominant
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001277259.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
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Benign
(Nov 20, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000168804.14
First in ClinVar: Jun 23, 2014 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 27173043, 28104484, 25145519, 25145518, 28254189, 27659478, 28182231, 31481236)
|
|
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Benign
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Brugada syndrome 8
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000288904.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
|
|
|
Benign
(Nov 24, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000735350.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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|
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001920219.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001740715.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
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Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001927012.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001954407.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Comment:
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
This variant is associated with the following publications: (PMID: 27173043, 28104484, 25145519, 25145518, 28254189, 27659478, 28182231, 31481236)
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Germline Functional Evidence
| 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. |
Comment:
HCN4: BS1, BS2
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
This variant is associated with the following publications: (PMID: 27173043, 28104484, 25145519, 25145518, 28254189, 27659478, 28182231, 31481236)
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Reply: A Distinct Cardiomyopathy: HCN4 Syndrome Comprising Myocardial Noncompaction, Bradycardia, Mitral Valve Defects, and Aortic Dilation. | Arbustini E | Journal of the American College of Cardiology | 2017 | PMID: 28254189 |
| A gain-of-function mutation in the cardiac pacemaker HCN4 channel increasing cAMP sensitivity is associated with familial Inappropriate Sinus Tachycardia. | Baruscotti M | European heart journal | 2017 | PMID: 28182231 |
| Sick sinus syndrome with HCN4 mutations shows early onset and frequent association with atrial fibrillation and left ventricular noncompaction. | Ishikawa T | Heart rhythm | 2017 | PMID: 28104484 |
| Left ventricular non-compaction and idiopathic dilated cardiomyopathy: the significant diagnostic value of longitudinal strain. | Tarando F | The international journal of cardiovascular imaging | 2017 | PMID: 27659478 |
| Dilation of the Aorta Ascendens Forms Part of the Clinical Spectrum of HCN4 Mutations. | Vermeer AMC | Journal of the American College of Cardiology | 2016 | PMID: 27173043 |
| Pacemaker activity of the human sinoatrial node: an update on the effects of mutations in HCN4 on the hyperpolarization-activated current. | Verkerk AO | International journal of molecular sciences | 2015 | PMID: 25642760 |
| Ion channel dysfunction associated with arrhythmia, ventricular noncompaction, and mitral valve prolapse: a new overlapping phenotype. | Towbin JA | Journal of the American College of Cardiology | 2014 | PMID: 25145519 |
| The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel. | Schweizer PA | Journal of the American College of Cardiology | 2014 | PMID: 25145518 |
| Interpreting secondary cardiac disease variants in an exome cohort. | Ng D | Circulation. Cardiovascular genetics | 2013 | PMID: 23861362 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HCN4 | - | - | - | - |
Text-mined citations for rs148398509 ...
HelpThese 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 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.