Submissions for variant NM_000335.5(SCN5A):c.1577G>A (p.Arg526His)

gnomAD frequency: 0.00003  dbSNP: rs45627438

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000713134	SCV000514539	uncertain significance	not provided	2024-04-04	criteria provided, single submitter	clinical testing	Observed in individuals reported to have HCM, DCM, and/or Brugada syndrome (Hershberger et al., 2008; Kapplinger et al., 2010; Sommariva et al., 2013; Alba et al., 2014; Priganc et al., 2016; Miszalski-Jamka et al., 2017; Berthome et al., 2019; Kuhnisch et al., 2019); Published functional studies are conflicting: some studies demonstrated that this variant results in loss of PKA-mediated phosyphorylation and dysregulation of trafficking and signaling, while other studies show function similar to wild type (Aiba et al., 2014; Hoshi et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 24795344, 19412328, 32048431, 24573164, 23414114, 20129283, 21726068, 23732518, 27554632, 25172307, 31333075, 23321620, 30193851, 28798025, 31568572, 33131149, 30203441, 32268277, 35163304, 33969014, 35932045)
Athena Diagnostics	RCV000713134	SCV000843706	uncertain significance	not provided	2017-09-11	criteria provided, single submitter	clinical testing
Klaassen Lab, Charite University Medicine Berlin	RCV000853128	SCV000995840	uncertain significance	Primary familial hypertrophic cardiomyopathy	2019-07-03	criteria provided, single submitter	research
Mendelics	RCV000987229	SCV001136478	uncertain significance	Brugada syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001842284	SCV001357909	uncertain significance	Cardiac arrhythmia	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 526 of the SCN5A protein. Histidine residue is tolerated in over 15 mammalian species, suggesting that this variant may be tolerated for SCN5A function. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have provided conflicting information about the effect of this variant on the SCN5A sodium channel function, with one study reporting insignificant impact (PMID: 24573164) and another study reporting reduced basal sodium current densities and reduced protein expression at the cell surface (PMID: 24795344). This variant has been reported in four individuals affected with Brugada syndrome (PMID 23321620, 24795344, 30193851, 32268277, 32893267), two individuals suspected of having Brugada syndrome (PMID: 20129283), one individual with unspecified arrhythmia (Mizusawa 2016, dissertation, University of Amsterdam), six individuals with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 19412328, 27554632, 31568572), and one individual affected with left ventricular hypertrabeculation (PMID: 28798025). This variant has also been identified in 15/274016 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000713134	SCV001383925	likely pathogenic	not provided	2025-01-29	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 526 of the SCN5A protein (p.Arg526His). 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 missense change has been observed in individuals with Brugada syndrome and/or dilated cardiomyopathy, hypertrophic cardiomyopathy, or left ventricular hypertrabeculation (PMID: 19412328, 20129283, 23321620, 24795344, 27554632, 28798025, 30193851, 31568572; internal data). ClinVar contains an entry for this variant (Variation ID: 67668). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 24573164, 24795344). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
All of Us Research Program, National Institutes of Health	RCV001842284	SCV004826954	uncertain significance	Cardiac arrhythmia	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 526 of the SCN5A protein. Histidine residue is tolerated in over 15 mammalian species, suggesting that this variant may be tolerated for SCN5A function. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that the variant does not cause a significant difference in recovery from inactivation and steady-state inactivation parameters (PMID: 24573164). However, the variant results in both reduced basal Na+ current densities, due to absence of phosphorylation and reduced cell surface channel expression, and absence of augmentation of current densities by beta-adrenergic stimulation (PMID: 24795344). Post-translational methylation of arginine at codon 526 has been proposed as a possible mechanism behind reduced sodium current in end-stage heart failure (PMID: 25172307). Clinical relevance of these functional observations is not known. This variant has been reported in a few individuals affected with Brugada syndrome (PMID: 24795344, 32268277, 32893267), two individuals suspected of having Brugada syndrome (PMID: 20129283), one individual with unspecified arrhythmia (Mizusawa 2016, dissertation, University of Amsterdam), four individuals with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 27554632, 31568572), and one individual affected with left ventricular hypertrabeculation (PMID: 28798025). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV004019034	SCV005031207	likely benign	Cardiovascular phenotype	2023-11-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Roden Lab, Vanderbilt University Medical Center	RCV000987229	SCV005200442	uncertain significance	Brugada syndrome 1		criteria provided, single submitter	research	We classified this variant using data from the calibrated functional assay 'ParSE-seq' (PMID: 37732247), population data, and in silico data within the ACMG v3 framework (PMID: 25741868)The SCN5A variant, 3-38604025-C-T was evaluated for association with the loss-of-function condition Brugada Syndrome.This Variant had an AF of 0.0000526 in gnomAD v3The in silico predictor SpliceAI scored the variant as 0.2278; normal <0.2, likely damaging >0.5.Using the functional RNA-splicing assay, ParSE-seq, the variant was evaluated to have an indeterminate impact on splicing following the Brnich et al. calibration framework (PMID: 31892348). In aggregate, we therefore classify this variant as VUS using these collective data.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058431	SCV000089951	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.