Submissions for variant NM_000335.5(SCN5A):c.4490T>C (p.Met1497Thr)

dbSNP: rs199473263

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183196	SCV000235614	uncertain significance	not provided	2022-05-17	criteria provided, single submitter	clinical testing	Reported in patients with LQTS in published literature; however detailed clinical information was not provided (Riuro et al., 2015; Napolitano et al., 2005); 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: 32268277, 23840796, 23663249, 26467377, 24667783, 16414944)
Invitae	RCV000183196	SCV000637156	uncertain significance	not provided	2019-05-03	criteria provided, single submitter	clinical testing	This variant identified in the SCN5A gene is located in the interdomain linker DIII/DIV region of the resulting protein (PMID: 25348405). For more information about the location of this variant, please visit www.invitae.com/SCN5A-topology. It is unclear how this variant impacts the function of this protein. 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. 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This variant has been reported in the literature in an individual referred for long QT syndrome genetic testing (PMID: 16414944).   ClinVar contains an entry for this variant (Variation ID: 67902). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with threonine at codon 1498 of the SCN5A protein (p.Met1498Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine.
Ambry Genetics	RCV000619022	SCV000737387	likely pathogenic	Cardiovascular phenotype	2019-06-10	criteria provided, single submitter	clinical testing	The p.M1498T variant (also known as c.4493T>C), located in coding exon 25 of the SCN5A gene, results from a T to C substitution at nucleotide position 4493. The methionine at codon 1498 is replaced by threonine, an amino acid with similar properties located in the cytoplasmic region linking transmembrane protein domains III and IV. This variant was previously described in a patient with long QT syndrome (Napolitano C et al. JAMA. 2005;294(23):2975-80). Additionally, other alterations involving the same amino acid position (p.M1498V c.4492A>G; p.M198R c.4493T>G) have been observed either in a patient from a study of long QT syndrome clinical genetic testing or in a family with sick sinus syndrome (Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Asadi M et al. Anatol J Cardiol, 2016 Mar;16:170-4). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058682	SCV000090202	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:16414944). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.