ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.1333C>G (p.His445Asp) (rs199473112)

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Total submissions: 6
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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 2020-09-08 criteria provided, single submitter clinical testing This sequence change replaces histidine with aspartic acid at codon 445 of the SCN5A protein (p.His445Asp). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant is present in population databases (rs199473112, ExAC 0.02%). This variant has been reported in individuals affected with Brugada syndrome and lone atrial fibrillation (PMID: 25650408, 30193851, 19808477). It was also shown to segregate with disease in a family affected with atrial fibrillation (PMID: 18378609). ClinVar contains an entry for this variant (Variation ID: 30046). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C2). 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. 5
Mendelics RCV000991041 SCV001142145 uncertain significance Brugada syndrome 1 2019-05-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV001188640 SCV001355726 uncertain significance Arrhythmia 2020-10-26 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 may alter voltage-dependence of activation, recovery and inactivation of the sodium channel (Gillani et al., 2010). This variant has been reported in an individual affected with Brugada syndrome (PMID: 25650408) and in two individuals affected with lone atrial fibrillation (PMID: 18378609, 19808477). This variant has been reported in three individuals from a family affected with atrial fibrillation (PMID: 18378609). 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.
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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