NM_005477.3(HCN4):c.3502_3505del (p.Phe1168fs) AND Brugada syndrome 8

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 31, 2024
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:: RCV000647239.9

Allele description [Variation Report for NM_005477.3(HCN4):c.3502_3505del (p.Phe1168fs)]

NM_005477.3(HCN4):c.3502_3505del (p.Phe1168fs)

Gene:

HCN4:hyperpolarization activated cyclic nucleotide gated potassium channel 4 [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

15q24.1

Genomic location:

Preferred name:

NM_005477.3(HCN4):c.3502_3505del (p.Phe1168fs)

HGVS:

NC_000015.10:g.73322588CAAA[1]
NG_009063.1:g.51670TTTG[1]
NM_005477.3:c.3502_3505delMANE SELECT
NP_005468.1:p.Phe1168fs
NC_000015.9:g.73614929CAAA[1]
NC_000015.9:g.73614929_73614932del
NM_005477.2:c.3502_3505del
NM_005477.2:c.3502_3505delTTTG

Protein change:

F1168fs

Links:

dbSNP: rs786205259

NCBI 1000 Genomes Browser:

rs786205259

Molecular consequence:

NM_005477.3:c.3502_3505del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000769028	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 31, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23861362, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000769028

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 31, 2024)

germline

clinical testing

PubMed (2)
[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

Interpreting secondary cardiac disease variants in an exome cohort.

Ng D, Johnston JJ, Teer JK, Singh LN, Peller LC, Wynter JS, Lewis KL, Cooper DN, Stenson PD, Mullikin JC, Biesecker LG; NIH Intramural Sequencing Center (NISC) Comparative Sequencing Program..

Circ Cardiovasc Genet. 2013 Aug;6(4):337-46. doi: 10.1161/CIRCGENETICS.113.000039. Epub 2013 Jul 16.

PubMed [citation]

PMID:: 23861362
PMCID:: PMC3887521

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000769028.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.Phe1168Glyfs*12) in the HCN4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 36 amino acid(s) of the HCN4 protein. This variant is present in population databases (rs771725926, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with sinus node disease (PMID: 23861362). ClinVar contains an entry for this variant (Variation ID: 191377). 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.

#	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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