Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000621795 | SCV000737964 | uncertain significance | Cardiovascular phenotype | 2017-03-22 | criteria provided, single submitter | clinical testing | The p.R811H variant (also known as c.2432G>A), located in coding exon 14 of the SCN5A gene, results from a G to A substitution at nucleotide position 2432. The arginine at codon 811 is replaced by histidine, an amino acid with highly similar properties. This variant was detected in a proband with Brugada syndrome, who also carried the p.R620H on the second allele. The proband inherited the p.R811H alteration from his father, who was asymptomatic but had a type I Brugada pattern on ECG. The proband's brother and the proband's twin daughters carried the p.R811H alteration, and had normal ECG results. The proband's mother had the p.R620H alteration and also had a normal ECG (Calloe K et al. Circ Arrhythm Electrophysiol, 2013 Feb;6:177-84). Induced pluripotent stem cells derived from the patient's skin fibroblast showed some differences in channel activity (Liang P et al. J. Am. Coll. Cardiol., 2016 Nov;68:2086-2096). In CHO-K1 cells, this p.R811H alteration resulted in reduced peak current density and negative shift of V1/2 of inactivation, while the p.R620H alteration appeared not to affect the channel activity or modified p.R811H when expressed at 1:1 ratio (Calloe K et al. Circ Arrhythm Electrophysiol, 2013 Feb;6:177-84). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Fulgent Genetics, |
RCV002506507 | SCV002814565 | uncertain significance | Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10 | 2021-08-20 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV003542307 | SCV003525142 | uncertain significance | not provided | 2022-06-25 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 23424222). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 23424222). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 519424). This variant is present in population databases (rs769349991, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 811 of the SCN5A protein (p.Arg811His). |
| Gene |
RCV003542307 | SCV005201200 | pathogenic | not provided | 2023-12-02 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect through significant loss of function in peak sodium current density and alteration of inactivation and recovery from inactivation (PMID: 23424222); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28573431, 27810048, 30662450, 34697415, 33131149, 30203441, 23424222, 35063694, 30079003) |