NM_005477.3(HCN4):c.1444G>A (p.Gly482Arg) AND Brugada syndrome 8

Clinical significance:Pathogenic (Last evaluated: Jul 21, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000647252.4

Allele description [Variation Report for NM_005477.3(HCN4):c.1444G>A (p.Gly482Arg)]

NM_005477.3(HCN4):c.1444G>A (p.Gly482Arg)

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.1444G>A (p.Gly482Arg)
HGVS:
  • NC_000015.10:g.73329719C>T
  • NG_009063.1:g.44546G>A
  • NM_005477.3:c.1444G>AMANE SELECT
  • NP_005468.1:p.Gly482Arg
  • NC_000015.9:g.73622060C>T
  • NM_005477.2:c.1444G>A
Protein change:
G482R
Links:
dbSNP: rs794727637
NCBI 1000 Genomes Browser:
rs794727637
Molecular consequence:
  • NM_005477.3:c.1444G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Brugada syndrome 8 (BRGDA8)
Identifiers:
MONDO: MONDO:0013148; MedGen: C2751083; Orphanet: 130; OMIM: 613123

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000769041Invitaecriteria provided, single submitter
Pathogenic
(Jul 21, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

HCN4 mutation as a molecular explanation on patients with bradycardia and non-compaction cardiomyopathy.

Millat G, Janin A, de Tauriac O, Roux A, Dauphin C.

Eur J Med Genet. 2015 Sep;58(9):439-42. doi: 10.1016/j.ejmg.2015.06.004. Epub 2015 Jul 21.

PubMed [citation]
PMID:
26206080

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
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000769041.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces glycine with arginine at codon 482 of the HCN4 protein (p.Gly482Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with sinus node dysfunction and left ventricular non compaction in several families (PMID: 26206080, 25145517, 25145518, 27173043). ClinVar contains an entry for this variant (Variation ID: 197253). Experimental studies have shown that this missense change causes a deleterious effect on protein function (PMID: 25145518). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Sep 24, 2021

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