Submissions for variant NM_000335.5(SCN5A):c.4745G>A (p.Arg1582His)

gnomAD frequency: 0.00002  dbSNP: rs199473621

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413021	SCV000490790	uncertain significance	not provided	2020-11-25	criteria provided, single submitter	clinical testing	Identified in association with Brugada syndrome (Kapplinger et al., 2010; Berthome et al., 2019) and HCM (van Lint et al., 2019) in the published literature; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID# 67921; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30662450, 20129283, 30193851, 30847666, 24136861)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455572	SCV000540287	uncertain significance	not specified	2016-10-20	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1-3 probands, no segregations, paralog variants in SCN1A associated with epilepsy
Labcorp Genetics (formerly Invitae), Labcorp	RCV000413021	SCV000825191	uncertain significance	not provided	2024-08-12	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 1583 of the SCN5A protein (p.Arg1583His). 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 individual(s) with clinical features of SCN5A-related conditions (PMID: 20129283, 25904541, 30193851, 30847666). ClinVar contains an entry for this variant (Variation ID: 67921). 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. This variant disrupts the p.Arg1583 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been observed in individuals with SCN5A-related conditions (PMID: 30193851), which suggests that this may be a clinically significant amino acid residue. 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.
All of Us Research Program, National Institutes of Health	RCV003996544	SCV004814576	uncertain significance	Cardiac arrhythmia	2024-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1583 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. This variant is found within a highly conserved transmembrane domain (a.a. 1530-1771). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a few individuals affected with Brugada syndrome (PMID: 24136861, 25904541, 32893267, 34147702), in an individual suspected of having Brugada syndrome (PMID: 20129283), and in an individual affected with hypertrophic cardiomyopathy (PMID: 30847666). This variant has been identified in 6/280512 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	RCV004019053	SCV004944524	uncertain significance	Cardiovascular phenotype	2020-10-21	criteria provided, single submitter	clinical testing	The c.4748G>A (p.R1583H) alteration is located in exon 27 (coding exon 26) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 4748, causing the arginine (R) at amino acid position 1583 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786346	SCV005399991	uncertain significance	Brugada syndrome 1	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-VUS. Following criteria are met: 0103 - Loss of function and gain of function are both known mechanisms of disease in this gene. Loss of function is usually associated with Brugada syndrome 1 (MIM#601144) and sick sinus syndrome (SSS) (MIM#608567), whereas gain of function is usually associated with long QT syndrome (LQTS) (MIM#603830). However, some variants simultaneously result in both a loss and gain of function effect, and have been observed in patients with LQTS, Brugada syndrome, SSS, and patients with a blended phenotype. Additionally, different studies have shown conflicting mechanisms in association with atrial fibrillation (MIM#614022) (PMID: 29806494, PMID: 19167345, PMID: 26798387). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are dominantly inherited, however, SSS can be caused by recessive variants (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine.(N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2: 6 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (p.(Arg1583Cys): 2 heterozygotes, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif. Variant is located in the ion transport domain (NCBI conserved domain), in an intracellular linker region of DIV between the S2 and S3 transmembrane domains. (N) 0708 - Comparable variants have conflicting previous evidence for pathogenicity. The p.(Arg1583Cys) variant has been reported in two individuals with Brugada syndrome where one carried a second SCN5A missense variant, and one individual with sudden cardiac death and cardiomyopathies who carried a second LMNA variant (PMIDs: 20129283, 31453232). In ClinVar, this variant has been submitted as likely pathogenic and as a variant of uncertain significance. (N) 0808 - Previous reports of pathogenicity are conflicting. This variant has been identified in one individual each with Brugada syndrome and hypertrophic cardiomyopathy, respectively (PMIDs: 20129283, 30847666). In ClinVar, this variant has been submitted as likely pathogenic and as a variant of uncertain significance. (N). 0905 - No segregation evidence has been identified for this variant in the literature. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058702	SCV000090222	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.