ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.3497_3500del (p.Ser1166fs) (rs774674047)

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Total submissions: 3
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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, Partners HealthCare 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 2020-09-24 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. This variant is present in population databases (rs774674047, ExAC 0.01%). This variant has not been reported in the literature in individuals with HCN4-related disease. ClinVar contains an entry for this variant (Variation ID: 190785). The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in HCN4 cause disease. 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.

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