Submissions for variant NM_000335.5(SCN5A):c.1595T>G (p.Phe532Cys)

gnomAD frequency: 0.00001  dbSNP: rs199473573

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182979	SCV000235378	uncertain significance	not provided	2020-07-16	criteria provided, single submitter	clinical testing	Reported in individuals with various cardiac phenotypes, including paroxysmal atrial fibrillation and atrial tachycardia, sudden infant death syndrome, and incomplete right bundle branch block with overall normal EKGs (Maekawa et al., 2005; Otagiri et al., 2008; Warring et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31043699, 29728395, 15996170, 18596570, 30662450, 29062695, 28341781)
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490338	SCV000267490	uncertain significance	SUDDEN INFANT DEATH SYNDROME	2016-03-18	criteria provided, single submitter	reference population
Color Diagnostics, LLC DBA Color Health	RCV001842287	SCV001342757	uncertain significance	Cardiac arrhythmia	2023-07-13	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with cysteine at codon 532 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes a reduction of sodium current density in transfected rat neonatal cardiomyocytes but no changes in channel function found in transfected human kidney cell line tsA-201 (PMID: 18596570, 34843967). This variant has been reported in three individuals affected with or suspected of having Brugada syndrome (PMID: 20129283, 28341781, 32893267), and in other individuals affected with arrhythmia (PMID: 15996170), sudden infant death syndrome (PMID: 18596570), or sudden unexpected death (PMID: 32449611). This variant has also been reported in 2 related individuals with normal electrocardiograms exhibiting no type 1 Brugada ECG pattern or any T-wave abnormalities (PMID: 29062695). This variant has been identified in 4/247568 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	RCV000182979	SCV002184813	uncertain significance	not provided	2024-02-24	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 532 of the SCN5A protein (p.Phe532Cys). This variant is present in population databases (rs199473573, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of Brugada syndrome (PMID: 15996170, 18596570, 20129283, 28341781). ClinVar contains an entry for this variant (Variation ID: 67671). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 18596570, 34843967). 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.
Fulgent Genetics, Fulgent Genetics	RCV002483110	SCV002777023	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	2024-05-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001842287	SCV004839433	uncertain significance	Cardiac arrhythmia	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with cysteine at codon 532 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes a reduction of sodium current density in transfected rat neonatal cardiomyocytes but no changes in channel function found in transfected human kidney cell line tsA-201 (PMID: 18596570, 34843967). This variant has been reported in three individuals affected with or suspected of having Brugada syndrome (PMID: 20129283, 28341781, 32893267), and in other individuals affected with arrhythmia (PMID: 15996170), sudden infant death syndrome (PMID: 18596570), or sudden unexpected death (PMID: 32449611). This variant has also been reported in 2 related individuals with normal electrocardiograms exhibiting no type 1 Brugada ECG pattern or any T-wave abnormalities (PMID: 29062695). This variant has been identified in 4/247568 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058434	SCV000089954	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:15996170;PMID:18596570;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.