NM_005477.3(HCN4):c.1241C>G (p.Ala414Gly) AND Sick sinus syndrome 2, autosomal dominant

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 26, 2014
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

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:: RCV000415571.2

Allele description [Variation Report for NM_005477.3(HCN4):c.1241C>G (p.Ala414Gly)]

NM_005477.3(HCN4):c.1241C>G (p.Ala414Gly)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

15q24.1

Genomic location:

Preferred name:

NM_005477.3(HCN4):c.1241C>G (p.Ala414Gly)

HGVS:

NC_000015.10:g.73332261G>C
NG_009063.1:g.42004C>G
NM_005477.3:c.1241C>GMANE SELECT
NP_005468.1:p.Ala414Gly
NC_000015.9:g.73624602G>C
NM_005477.2:c.1241C>G

Protein change:

A414G; ALA414GLY

Links:

OMIM: 605206.0010; dbSNP: rs1057519276

NCBI 1000 Genomes Browser:

rs1057519276

Molecular consequence:

NM_005477.3:c.1241C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Sick sinus syndrome 2, autosomal dominant (SSS2)
Synonyms:: ATRIAL FIBRILLATION WITH BRADYARRHYTHMIA; SINUS BRADYCARDIA SYNDROME, FAMILIAL, AUTOSOMAL DOMINANT; SINUS NODE DISEASE, FAMILIAL, AUTOSOMAL DOMINANT; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008102; MedGen: C1834144; Orphanet: 166282; OMIM: 163800

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000493947	OMIM	no assertion criteria provided	Pathogenic (Aug 26, 2014)	germline	literature only	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000493947

OMIM

no assertion criteria provided

Pathogenic
(Aug 26, 2014)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy.

Milano A, Vermeer AM, Lodder EM, Barc J, Verkerk AO, Postma AV, van der Bilt IA, Baars MJ, van Haelst PL, Caliskan K, Hoedemaekers YM, Le Scouarnec S, Redon R, Pinto YM, Christiaans I, Wilde AA, Bezzina CR.

J Am Coll Cardiol. 2014 Aug 26;64(8):745-56. doi: 10.1016/j.jacc.2014.05.045.

PubMed [citation]

PMID:: 25145517

Details of each submission

From OMIM, SCV000493947.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a father and 2 sons (family C) with bradycardia and left ventricular noncompaction (SSS2; 163800), Milano et al. (2014) identified heterozygosity for a c.1241C-G transversion in exon 3 of the HCN4 gene, resulting in an ala414-to-gly (A414G) substitution at a highly conserved residue between the S4 and S5 transmembrane domains. The mutation was not found in 500 Dutch controls or in the Exome Sequencing Project database. Functional analysis in CHO cells showed a large negative shift in voltage dependence of activation with mutant channels compared to wildtype, resulting in significantly lower current density, consistent with the observed bradycardia. Both sons also exhibited left ventricular hypertrophy, with interventricular septa measuring 13 mm.

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

Last Updated: Jun 9, 2024

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