Submissions for variant NM_005477.3(HCN4):c.1471G>A (p.Asp491Asn)

dbSNP: rs1060500107

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000462048	SCV000541570	likely pathogenic	Brugada syndrome 8	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 491 of the HCN4 protein (p.Asp491Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of HCN4-related conditions (PMID: 30847666, 34088380; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 404133). 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 expected to disrupt HCN4 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004533143	SCV004115407	uncertain significance	HCN4-related disorder	2022-09-07	criteria provided, single submitter	clinical testing	The HCN4 c.1471G>A variant is predicted to result in the amino acid substitution p.Asp491Asn. This variant was reported in at least five individuals with noncompaction cardiomyopathy or arrhythmias (Supplementary File 2 - van Lint et al. 2019. PubMed ID: 30847666; Cambon-Viala et al. 2021. PubMed ID: 34088380). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Although we suspect that this variant may be pathogenic, 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	RCV001700182	SCV001926152	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001700182	SCV001963192	pathogenic	not provided		no assertion criteria provided	clinical testing