ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.2995C>T (p.Arg999Trp)

gnomAD frequency: 0.00004  dbSNP: rs538668505
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000697356 SCV000825959 uncertain significance Brugada syndrome 8 2025-01-01 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 999 of the HCN4 protein (p.Arg999Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 575202). 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 not expected to disrupt HCN4 protein function with a negative 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.
GeneDx RCV001585639 SCV001819402 uncertain significance not provided 2019-09-20 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 575202; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Ambry Genetics RCV002440489 SCV002746938 uncertain significance Cardiovascular phenotype 2024-08-26 criteria provided, single submitter clinical testing The c.2995C>T (p.R999W) alteration is located in exon 8 (coding exon 8) of the HCN4 gene. This alteration results from a C to T substitution at nucleotide position 2995, causing the arginine (R) at amino acid position 999 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002485699 SCV002776869 uncertain significance Sick sinus syndrome 2, autosomal dominant; Brugada syndrome 8; Epilepsy, idiopathic generalized, susceptibility to, 18 2021-10-04 criteria provided, single submitter clinical testing

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