ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.1333C>G (p.His445Asp)

gnomAD frequency: 0.00011  dbSNP: rs199473112
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000418451 SCV000514537 uncertain significance not provided 2020-02-26 criteria provided, single submitter clinical testing Identified in patients with LQTS, atrial fibrillation, Brugada syndrome, or sudden infant death either tested at GeneDx or in the published literature (Darbar et al., 2008; Le Scouarnec et al., 2015; Campuzano et al., 2018); however, some individuals harbor additional variants that could explain their phenotype; Observed to segregate with atrial fibrillation in one proband's affected father and brother (Darbar et al., 2008); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 30046; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 19808477, 22581653, 25650408, 18378609, 28150151, 30086531, 28086167, 30193851)
Invitae RCV000458775 SCV000545010 uncertain significance Brugada syndrome 2022-09-28 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 445 of the SCN5A protein (p.His445Asp). This variant is present in population databases (rs199473112, gnomAD 0.008%). This missense change has been observed in individual(s) with Brugada syndrome and lone atrial fibrillation (PMID: 18378609, 19808477, 25650408, 30193851). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30046). 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: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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.
Mendelics RCV000991041 SCV001142145 uncertain significance Brugada syndrome 1 2019-05-28 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001841253 SCV001355726 uncertain significance Cardiac arrhythmia 2023-05-15 criteria provided, single submitter clinical testing This missense variant replaces histidine with aspartic acid at codon 445 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant alters voltage-dependence of activation, recovery and inactivation of the sodium channel (Gillani et al., 2010). This variant has been reported in individuals affected with atrial fibrillation (PMID: 18378609, 19808477), Brugada syndrome (PMID: 25650408, 30193851, 32893267), dilated cardiomyopathy (PMID: 32826072), and sudden death in infancy (PMID: 30086531). This variant has also been identified in 14/275240 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.
Ambry Genetics RCV002381260 SCV002690341 uncertain significance Cardiovascular phenotype 2022-03-08 criteria provided, single submitter clinical testing The p.H445D variant (also known as c.1333C>G), located in coding exon 9 of the SCN5A gene, results from a C to G substitution at nucleotide position 1333. The histidine at codon 445 is replaced by aspartic acid, an amino acid with similar properties. This variant has been detected in individuals from various cohorts including sudden infant death, sudden death, arrhythmia, and Brugada syndrome; however, clinical details were limited, some reports may overlap, and additional variants in were also detected in some cases (Le Scouarnec S et al. Hum Mol Genet, 2015 May;24:2757-63; Campuzano O et al. Forensic Sci Int, 2017 Feb;271:120-125; Amin AS et al. Int J Cardiol, 2018 Sep;266:128-132; Campuzano O et al. Forensic Sci Int Genet, 2018 11;37:54-63; Berthome P et al. Heart Rhythm, 2019 02;16:260-267). This variant has also been reported in association with atrial fibrillation and, in one family, was detected in three affected individuals (Darbar D et al. Circulation, 2008 Apr;117:1927-35; Watanabe H et al. Circ Arrhythm Electrophysiol, 2009 Jun;2:268-75). This amino acid position is not well 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, Fulgent Genetics RCV002504819 SCV002815937 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 2022-02-14 criteria provided, single submitter clinical testing
OMIM RCV000022948 SCV000044239 pathogenic Atrial fibrillation, familial, 10 2008-04-15 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust RCV000058414 SCV000089934 not provided Atrial fibrillation no assertion provided literature only This variant has been reported as associated with Atrial fibrillation in the following publications (PMID:18378609). 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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