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

dbSNP: rs786205259

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171563	SCV000050608	uncertain significance	Sinoatrial node disorder	2018-04-05	criteria provided, single submitter	research
Invitae	RCV000647239	SCV000769028	uncertain significance	Brugada syndrome 8	2024-01-31	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV001530062	SCV001815061	uncertain significance	not provided	2023-05-31	criteria provided, single submitter	clinical testing	Reported in an individual in the ClinSeq Project who had a normal ECG and echocardiogram and no family history of arrhythmia or sudden cardiac death; denoted as c.3498_3501del due to alternate nomenclature (Ng et al., 2013); Has been reported as a variant of uncertain significance in an individual with Brugada syndrome (Sarquella-Brugada et al., 2021); Frameshift variant predicted to result in protein truncation as the last 36 amino acids are replaced with 11 different amino acids; This variant is associated with the following publications: (PMID: 26046366, 26582918, 23861362, 34546463)
Ambry Genetics	RCV002453588	SCV002614724	uncertain significance	Cardiovascular phenotype	2023-04-27	criteria provided, single submitter	clinical testing	The c.3502_3505delTTTG variant, located in coding exon 8 of the HCN4 gene, results from a deletion of 4 nucleotides at nucleotide positions 3502 to 3505, causing a translational frameshift with a predicted alternate stop codon (p.F1168Gfs*12). This alteration has been reported as a secondary cardiac variant in an exome cohort, and has been detected in individuals reported to have Brugada syndrome and atrial fibrillation; however, clinical details were limited and additional variants in arrhythmia-associated genes were detected in some cases (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46; van Lint FHM et al. Neth Heart J. 2019 Jun;27(6):304-309; Sarquella-Brugada G et al. Hum Genet, 2022 Oct;141(10):1579-1589). This alteration is expected to result in protein truncation or nonsense-mediated mRNA decay. However, loss of function of HCN4 has not been established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002478543	SCV002796986	uncertain significance	Sick sinus syndrome 2, autosomal dominant; Brugada syndrome 8; Epilepsy, idiopathic generalized, susceptibility to, 18	2022-01-04	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001530062	SCV001744623	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001530062	SCV001925615	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001530062	SCV001954051	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001530062	SCV001972400	uncertain significance	not provided		no assertion criteria provided	clinical testing