NM_005477.3(HCN4):c.3502_3505del (p.Phe1168fs) AND Cardiovascular phenotype

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Apr 27, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002453588.3

Allele description [Variation Report for NM_005477.3(HCN4):c.3502_3505del (p.Phe1168fs)]

NM_005477.3(HCN4):c.3502_3505del (p.Phe1168fs)

Gene:

HCN4:hyperpolarization activated cyclic nucleotide gated potassium channel 4 [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

15q24.1

Genomic location:

Preferred name:

NM_005477.3(HCN4):c.3502_3505del (p.Phe1168fs)

HGVS:

NC_000015.10:g.73322588CAAA[1]
NG_009063.1:g.51670TTTG[1]
NM_005477.3:c.3502_3505delMANE SELECT
NP_005468.1:p.Phe1168fs
NC_000015.9:g.73614929CAAA[1]
NC_000015.9:g.73614929_73614932del
NM_005477.2:c.3502_3505del
NM_005477.2:c.3502_3505delTTTG

Protein change:

F1168fs

Links:

dbSNP: rs786205259

NCBI 1000 Genomes Browser:

rs786205259

Molecular consequence:

NM_005477.3:c.3502_3505del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002614724	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Apr 27, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23861362, 30847666, 34546463 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002614724

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Apr 27, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Interpreting secondary cardiac disease variants in an exome cohort.

Ng D, Johnston JJ, Teer JK, Singh LN, Peller LC, Wynter JS, Lewis KL, Cooper DN, Stenson PD, Mullikin JC, Biesecker LG; NIH Intramural Sequencing Center (NISC) Comparative Sequencing Program..

Circ Cardiovasc Genet. 2013 Aug;6(4):337-46. doi: 10.1161/CIRCGENETICS.113.000039. Epub 2013 Jul 16.

PubMed [citation]

PMID:: 23861362
PMCID:: PMC3887521

Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance.

van Lint FHM, Mook ORF, Alders M, Bikker H, Lekanne Dit Deprez RH, Christiaans I.

Neth Heart J. 2019 Jun;27(6):304-309. doi: 10.1007/s12471-019-1250-5.

PubMed [citation]

PMID:: 30847666
PMCID:: PMC6533346

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV002614724.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The c.3502_3505delTTTG variant, located in coding exon 8 of the HCN4 gene, results from a deletion of 4 nucleotides at nucleotide positions 3502 to 3505, causing a translational frameshift with a predicted alternate stop codon (p.F1168Gfs*12). This alteration has been reported as a secondary cardiac variant in an exome cohort, and has been detected in individuals reported to have Brugada syndrome and atrial fibrillation; however, clinical details were limited and additional variants in arrhythmia-associated genes were detected in some cases (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46; van Lint FHM et al. Neth Heart J. 2019 Jun;27(6):304-309; Sarquella-Brugada G et al. Hum Genet, 2022 Oct;141(10):1579-1589). This alteration is expected to result in protein truncation or nonsense-mediated mRNA decay. However, loss of function of HCN4 has not been established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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