Submissions for variant NM_005477.3(HCN4):c.2669C>T (p.Pro890Leu)

gnomAD frequency: 0.00008  dbSNP: rs758929649

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000647237	SCV000769026	uncertain significance	Brugada syndrome 8	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 890 of the HCN4 protein (p.Pro890Leu). This variant is present in population databases (rs758929649, gnomAD 0.005%). 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: 538081). 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 with a negative predictive value of 80%. 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	RCV001584491	SCV001813450	uncertain significance	not provided	2022-11-30	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function
Ambry Genetics	RCV002424488	SCV002741283	uncertain significance	Cardiovascular phenotype	2022-12-17	criteria provided, single submitter	clinical testing	The p.P890L variant (also known as c.2669C>T), located in coding exon 8 of the HCN4 gene, results from a C to T substitution at nucleotide position 2669. The proline at codon 890 is replaced by leucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and leucine is the reference amino acid in other 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.
PreventionGenetics, part of Exact Sciences	RCV003424230	SCV004117416	uncertain significance	HCN4-related condition	2023-09-24	criteria provided, single submitter	clinical testing	The HCN4 c.2669C>T variant is predicted to result in the amino acid substitution p.Pro890Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0044% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-73615765-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Clinical Genetics, Academic Medical Center	RCV001584491	SCV001923829	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001584491	SCV001972569	uncertain significance	not provided		no assertion criteria provided	clinical testing