Submissions for variant NM_005477.3(HCN4):c.3497_3500del (p.Ser1166fs)

dbSNP: rs774674047

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000767026	SCV000223504	uncertain significance	not provided	2016-09-21	criteria provided, single submitter	clinical testing	The c.3497_c.3500delCTTT variant in the HCN4 gene has not been reported as a disease-causing mutation or as a benign polymorphism, to our knowledge. This variant causes a shift in reading frame starting at codon Serine 1166, changing it to a Cysteine, and creating a premature stop codon at position 14 of the new reading frame, denoted p.Ser1166CysfsX14. This variant is expected to result in an abnormal, truncated protein product. However, the majority of mutations in HCN4 are missense changes indicating haploinsufficiency of HCN4 may not be sufficient to cause an arrhythmia phenotype. With the information available at this time, we cannot definitively determine if c.3497_c.3500delCTTT is a disease-causing mutation or a rare benign variant.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000170944	SCV000539275	uncertain significance	not specified	2016-07-26	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: LOF in last exon, and there is not enough evidence to support pathogenicity of LOF variants for this gene
Invitae	RCV000527488	SCV000648466	uncertain significance	Brugada syndrome 8	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1166Cysfs*14) in the HCN4 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in HCN4 cause disease. This variant is present in population databases (rs774674047, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with HCN4-related conditions. ClinVar contains an entry for this variant (Variation ID: 190785). 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.
AiLife Diagnostics, AiLife Diagnostics	RCV000767026	SCV002502322	uncertain significance	not provided	2022-02-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002453582	SCV002617252	uncertain significance	Cardiovascular phenotype	2022-11-29	criteria provided, single submitter	clinical testing	The c.3497_3500delCTTT variant, located in coding exon 8 of the HCN4 gene, results from a deletion of 4 nucleotides at nucleotide positions 3497 to 3500, causing a translational frameshift with a predicted alternate stop codon (p.S1166Cfs*14). This alteration occurs at the 3' terminus of theHCN4 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 38 amino acids (3%) of the protein. The exact functional effect of this alteration is unknown. In addition, 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	RCV002485072	SCV002776866	uncertain significance	Sick sinus syndrome 2, autosomal dominant; Brugada syndrome 8; Epilepsy, idiopathic generalized, susceptibility to, 18	2021-12-27	criteria provided, single submitter	clinical testing