ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.1577G>A (p.Arg526His) (rs45627438)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000713134 SCV000514539 uncertain significance not provided 2018-04-21 criteria provided, single submitter clinical testing The R526H variant in the SCN5A gene has been reported in individuals with variable cardiac phenotypes, including arrhythmia and cardiomyopathy (Hershberger et al., 2008; Kapplinger et al., 2010; Aiba et al., 2014; Priganc et al., 2016). One individual with a history of synope and a Brugada type 1 EKG pattern inherited the variant from mother with recurrent syncope and suggestive, though not diagnostic, EKG abnormalities (Aiba et al., 2014). The proband's sister also harbored the variant and was found to have right bundle branch block. Family studies were not available for other probands with cardiac phenotypes reported in the literature. The R526H variant was not observed with any significant frequency in approximately 6200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.The R526 variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to arginine are tolerated across species and H526 is wild-type in multiple other mammalian species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The R526H variant is located in the linker region between domains I and II of the Nav1.5 protein. Proteomic studies using mass spectroscopy identified R526 as a post-translational methylation site in HEK293 cells and in cardiomyocytes from heart failure patients (Beltran-Alvarez et al., 2011; Beltran-Alvarez et al., 2014). It was suggested that interference of this post-translational modification may result in an arrhythmia phenotype, however, the exact disease mechanism, if any, is not known. In neonatal rat cardiomyocytes expressing R526H, Aiba et al. (2014) demonstrated reduced cell surface expression and channel current density. However, Hoshi et al. (2014) found differences in peak current densities from wild-type were not significant.
Athena Diagnostics Inc 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
CeGaT Praxis fuer Humangenetik Tuebingen RCV000713134 SCV001153879 uncertain significance not provided 2018-06-01 criteria provided, single submitter clinical testing
Color RCV001190424 SCV001357909 uncertain significance Arrhythmia 2019-08-27 criteria provided, single submitter clinical testing
Invitae RCV000058431 SCV001383925 uncertain significance Brugada syndrome 2019-08-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 526 of the SCN5A protein (p.Arg526His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs45627438, ExAC 0.02%). This variant has been observed in individuals affected with Brugada syndrome, dilated cardiomyopathy, hypertrophic cardiomyopathy, or left ventricular hypertrabeculation (PMID: 20129283, 23321620, 24795344, 27554632, 19412328, 28798025). ClinVar contains an entry for this variant (Variation ID: 67668). This variant has been reported to have conflicting or insufficient data to determine the effect on SCN5A protein function (PMID: 24795344, 24573164). 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.
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.

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