Submissions for variant NM_000335.5(SCN5A):c.4456A>C (p.Met1486Leu)

gnomAD frequency: 0.00005  dbSNP: rs199473258

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002223185	SCV000937145	uncertain significance	not provided	2023-02-22	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1487 of the SCN5A protein (p.Met1487Leu). This variant is present in population databases (rs199473258, gnomAD 0.01%). This missense change has been observed in individual(s) with long QT syndrome and in an individual who suffered sudden unexplained death (PMID: 19716085, 29247119). ClinVar contains an entry for this variant (Variation ID: 67895). 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 tolerated. 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.
Color Diagnostics, LLC DBA Color Health	RCV001842364	SCV001342752	uncertain significance	Cardiac arrhythmia	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with leucine at codon 1487 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual referred for long QT syndrome genetic test (PMID: 19716085) and one case of sudden unexplained death (PMID: 24631775, 29247119). This variant has been identified in 3/282820 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.
AiLife Diagnostics, AiLife Diagnostics	RCV002223185	SCV002501781	uncertain significance	not provided	2021-07-23	criteria provided, single submitter	clinical testing
GeneDx	RCV002223185	SCV002576136	uncertain significance	not provided	2024-02-06	criteria provided, single submitter	clinical testing	Identified in a patient referred for long QT syndrome testing, however, no clinical information was provided (PMID: 19716085); Identified in two cases with sudden unexpected death, however, detailed clinical and segregation information was not available (PMID: 24631775, 29247119); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32569262, 29247119, 28316956, 19716085, 24631775, 22581653, 30669290)
Fulgent Genetics, Fulgent Genetics	RCV002490660	SCV002779727	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	2021-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004019051	SCV004943838	uncertain significance	Cardiovascular phenotype	2022-09-30	criteria provided, single submitter	clinical testing	The c.4459A>C (p.M1487L) alteration is located in exon 26 (coding exon 25) of the SCN5A gene. This alteration results from a A to C substitution at nucleotide position 4459, causing the methionine (M) at amino acid position 1487 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058675	SCV000090195	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.