Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000621795 | SCV000737964 | uncertain significance | Cardiovascular phenotype | 2024-08-22 | 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 trans with a second SCN5A variant (p.R620H) in a proband with Brugada syndrome (BrS). The proband's father who had only the p.R811H variant was asymptomatic but had a type I BrS pattern on ECG. The proband's brother, also with only the p.R811H variant, had a normal ECG. The proband's mother and daughters had only the p.R620H variant and were asymptomatic with normal ECGs (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 in vitro studies by one group, the 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 channel activity nor modify p.R811H when the variants were co-expressed (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 | 2024-11-10 | criteria provided, single submitter | clinical testing | 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). This variant is present in population databases (rs769349991, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 23424222, 35063694). ClinVar contains an entry for this variant (Variation ID: 519424). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN5A function (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. |
| 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) |