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

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 19, 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:: RCV000647252.8

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000769041	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 19, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25145517, 26206080, 27173043, 25145518, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000769041

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 19, 2023)

germline

clinical testing

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

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

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

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

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000769041.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 482 of the HCN4 protein (p.Gly482Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with sinus node dysfunction and left ventricular non compaction (PMID: 25145517, 25145518, 26206080, 27173043). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 197253). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HCN4 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HCN4 function (PMID: 25145518). For these reasons, this variant has been classified as Pathogenic.

#	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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