Submissions for variant NM_005477.3(HCN4):c.3209G>A (p.Gly1070Asp)

gnomAD frequency: 0.00004  dbSNP: rs772839442

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465826	SCV000541573	uncertain significance	Brugada syndrome 8	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1070 of the HCN4 protein (p.Gly1070Asp). 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: 404136). 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 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.
MGZ Medical Genetics Center	RCV002289585	SCV002580657	uncertain significance	Sick sinus syndrome 2, autosomal dominant	2022-01-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002446767	SCV002611721	uncertain significance	Cardiovascular phenotype	2022-02-25	criteria provided, single submitter	clinical testing	The p.G1070D variant (also known as c.3209G>A), located in coding exon 8 of the HCN4 gene, results from a G to A substitution at nucleotide position 3209. The glycine at codon 1070 is replaced by aspartic acid, an amino acid with similar properties. This variant was detected in a cardiomyopathy/arrhythmia genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000786319	SCV004132793	uncertain significance	not provided	2022-06-01	criteria provided, single submitter	clinical testing	HCN4: PP3
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786319	SCV000925094	uncertain significance	not provided	2018-01-19	no assertion criteria provided	provider interpretation
Clinical Genetics, Academic Medical Center	RCV000786319	SCV001918508	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000786319	SCV001963159	uncertain significance	not provided		no assertion criteria provided	clinical testing