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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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000493947OMIM
no assertion criteria provided
Pathogenic
(Aug 26, 2014) 		germlineliterature only

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 9, 2024