Submissions for variant NM_000335.5(SCN5A):c.3844C>A (p.Leu1282Met)

dbSNP: rs199473216

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000221645	SCV000272413	uncertain significance	not specified	2015-07-10	criteria provided, single submitter	clinical testing	The p.Leu1283Met variant in SCN5A has been identified in 1 individual tested for Long QT syndrome (specific phenotype information was not provided; Kapplinger 2 009). This variant was not identified in large population studies, though has be en listed in dbSNP without frequency information (rs199473216). Computational pr ediction tools and conservation analysis suggest that this variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In summary, while there is some suspicion for a pathogenic role, the cli nical significance of the p.Leu1283Met variant is uncertain.
Color Diagnostics, LLC DBA Color Health	RCV001842351	SCV001352008	uncertain significance	Cardiac arrhythmia	2020-03-18	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with methionine at codon 1283 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 1 individual referred for the long QT syndrome genetic test (PMID: 19716085). This variant has not been identified 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.
Invitae	RCV003556151	SCV004292664	uncertain significance	not provided	2023-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1283 of the SCN5A protein (p.Leu1283Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of long QT syndrome (LQTS) (PMID: 19716085, 25904541). ClinVar contains an entry for this variant (Variation ID: 67831). 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. 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058608	SCV000090128	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.