NM_005477.3(HCN4):c.3599_3600inv (p.Pro1200Leu) AND Brugada syndrome 8

Clinical significance:Uncertain significance (Last evaluated: Apr 2, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_005477.3(HCN4):c.3599_3600inv (p.Pro1200Leu)]

NM_005477.3(HCN4):c.3599_3600inv (p.Pro1200Leu)

HCN4:hyperpolarization activated cyclic nucleotide gated potassium channel 4 [Gene - OMIM - HGNC]
Variant type:
Cytogenetic location:
Genomic location:
Preferred name:
NM_005477.3(HCN4):c.3599_3600inv (p.Pro1200Leu)
  • NC_000015.10:g.73322493_73322494inv
  • NG_009063.1:g.51771_51772inv
  • NM_005477.3:c.3599_3600invMANE SELECT
  • NP_005468.1:p.Pro1200Leu
  • NC_000015.9:g.73614834_73614835inv
Protein change:
Molecular consequence:
  • NM_005477.3:c.3599_3600inv - missense variant - [Sequence Ontology: SO:0001583]


Brugada syndrome 8 (BRGDA8)
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)
SCV000826097Invitaecriteria provided, single submitter
Uncertain significance
(Apr 2, 2018)
germlineclinical testing

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

Summary from all submissions

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



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]

Details of each submission

From Invitae, SCV000826097.1

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


This sequence change replaces proline with leucine at codon 1200 of the HCN4 protein (p.Pro1200Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is reported as two separate single-nucleotide changes in population databases (c.3599C>T, ExAC 0.03% and c.3600A>G, ExAC 96%). However, in the read data for 5/5 individuals displayed in the ExAC browser, these two variants are in cis. This recapitulates the variant observed here (c.3599_3600delinsTG) and indicates that this variant is likely present in the population databases at 0.03%. This variant has not been reported in the literature in individuals with HCN4-related disease. 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. 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.

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

Last Updated: Oct 7, 2021

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