Submissions for variant NM_005477.3(HCN4):c.1796C>T (p.Ala599Val)

gnomAD frequency: 0.00001  dbSNP: rs775019344

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001294860	SCV001483755	uncertain significance	Brugada syndrome 8	2024-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 599 of the HCN4 protein (p.Ala599Val). This variant is present in population databases (rs775019344, gnomAD 0.003%). 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: 998936). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt HCN4 protein function with a positive predictive value of 95%. 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.
Fulgent Genetics, Fulgent Genetics	RCV002499539	SCV002812668	uncertain significance	Sick sinus syndrome 2, autosomal dominant; Brugada syndrome 8; Epilepsy, idiopathic generalized, susceptibility to, 18	2021-08-10	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV001796427	SCV002034637	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001796427	SCV002035020	uncertain significance	not provided		no assertion criteria provided	clinical testing