NM_005477.3(HCN4):c.2804C>A (p.Ser935Tyr) AND Brugada syndrome 8

Clinical significance:Uncertain significance (Last evaluated: Oct 19, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000546891.4

Allele description [Variation Report for NM_005477.3(HCN4):c.2804C>A (p.Ser935Tyr)]

NM_005477.3(HCN4):c.2804C>A (p.Ser935Tyr)

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.2804C>A (p.Ser935Tyr)
HGVS:
  • NC_000015.10:g.73323289G>T
  • NG_009063.1:g.50976C>A
  • NM_005477.3:c.2804C>AMANE SELECT
  • NP_005468.1:p.Ser935Tyr
  • NC_000015.9:g.73615630G>T
  • NM_005477.2:c.2804C>A
Protein change:
S935Y
Links:
dbSNP: rs775803239
NCBI 1000 Genomes Browser:
rs775803239
Molecular consequence:
  • NM_005477.3:c.2804C>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
SCV000648450Invitaecriteria provided, single submitter
Uncertain significance
(Oct 19, 2020)
germlineclinical testing

PubMed (2)
[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

Functional reclassification of variants of uncertain significance in the HCN4 gene identified in sudden unexpected death.

Dong J, Subbotina E, Williams N, Sampson BA, Tang Y, Coetzee WA.

Pacing Clin Electrophysiol. 2019 Feb;42(2):275-282. doi: 10.1111/pace.13593. Epub 2019 Jan 4.

PubMed [citation]
PMID:
30578647

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000648450.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces serine with tyrosine at codon 935 of the HCN4 protein (p.Ser935Tyr). The serine residue is highly conserved and there is a large physicochemical difference between serine and tyrosine. This variant is present in population databases (rs775803239, ExAC 0.05%). This variant has been observed in an individual who suffered a sudden death (PMID: 30578647). ClinVar contains an entry for this variant (Variation ID: 470659). This variant has been reported to not to substantially affect HCN4 protein function (PMID: 30578647). 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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