NM_005477.3(HCN4):c.1439G>T (p.Gly480Val) AND Brugada syndrome 8

Clinical significance:Uncertain significance (Last evaluated: Oct 6, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000471436.3

Allele description [Variation Report for NM_005477.3(HCN4):c.1439G>T (p.Gly480Val)]

NM_005477.3(HCN4):c.1439G>T (p.Gly480Val)

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.1439G>T (p.Gly480Val)
HGVS:
  • NC_000015.10:g.73329724C>A
  • NG_009063.1:g.44541G>T
  • NM_005477.3:c.1439G>TMANE SELECT
  • NP_005468.1:p.Gly480Val
  • NC_000015.9:g.73622065C>A
  • NM_005477.2:c.1439G>T
Protein change:
G480V
Links:
dbSNP: rs1060500103
NCBI 1000 Genomes Browser:
rs1060500103
Molecular consequence:
  • NM_005477.3:c.1439G>T - 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
SCV000541551Invitaecriteria provided, single submitter
Uncertain significance
(Oct 6, 2020)
germlineclinical testing

PubMed (3)
[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

Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia.

Nof E, Luria D, Brass D, Marek D, Lahat H, Reznik-Wolf H, Pras E, Dascal N, Eldar M, Glikson M.

Circulation. 2007 Jul 31;116(5):463-70. Epub 2007 Jul 23.

PubMed [citation]
PMID:
17646576

Pacemaker activity of the human sinoatrial node: effects of HCN4 mutations on the hyperpolarization-activated current.

Verkerk AO, Wilders R.

Europace. 2014 Mar;16(3):384-95. doi: 10.1093/europace/eut348. Review.

PubMed [citation]
PMID:
24569893
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000541551.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces glycine with valine at codon 480 of the HCN4 protein (p.Gly480Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with HCN4-related conditions. ClinVar contains an entry for this variant (Variation ID: 404118). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Gly480 amino acid residue in HCN4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17646576, 24569893). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Oct 7, 2021

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