ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.2875C>G (p.Leu959Val)

gnomAD frequency: 0.00002  dbSNP: rs1057524285
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000444935 SCV000535080 uncertain significance not provided 2020-07-22 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 391911; Landrum et al., 2016)
Invitae RCV000560748 SCV000648454 uncertain significance Brugada syndrome 8 2022-03-05 criteria provided, single submitter clinical testing 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HCN4 protein function. ClinVar contains an entry for this variant (Variation ID: 391911). This variant has not been reported in the literature in individuals affected with HCN4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 959 of the HCN4 protein (p.Leu959Val).
Ambry Genetics RCV002436351 SCV002751124 uncertain significance Cardiovascular phenotype 2019-08-13 criteria provided, single submitter clinical testing The p.L959V variant (also known as c.2875C>G), located in coding exon 8 of the HCN4 gene, results from a C to G substitution at nucleotide position 2875. The leucine at codon 959 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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