Submissions for variant NM_000335.5(SCN5A):c.2542A>T (p.Ile848Phe)

gnomAD frequency: 0.00001  dbSNP: rs199473166

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766791	SCV000235410	uncertain significance	not provided	2024-05-09	criteria provided, single submitter	clinical testing	Has been reported in association with LQTS (PMID: 19716085); 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: 34930020, 25904541, 19716085)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000183004	SCV000540282	uncertain significance	not specified	2016-06-23	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: Only 1 report; ClinVar: P by GeneDx and Royal Brompton
Labcorp Genetics (formerly Invitae), Labcorp	RCV000766791	SCV000545035	uncertain significance	not provided	2024-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 848 of the SCN5A protein (p.Ile848Phe). This variant is present in population databases (rs199473166, gnomAD 0.0009%). This missense change has been observed in individual(s) with long QT syndrome (LQTS) and referred for LQTS testing (PMID: 19716085, 25904541, 34930020). ClinVar contains an entry for this variant (Variation ID: 67740). 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 have shown that this missense change affects SCN5A function (PMID: 34930020). 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	RCV001842316	SCV001357910	uncertain significance	Cardiac arrhythmia	2023-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with phenylalanine at codon 848 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). A functional study has shown that this variant causes a reduction in channel peak current density when expressed in HEK293 cells (PMID: 34930020). This variant has been reported in individual(s) suspected of having long QT syndrome (PMID: 19716085, 25904541) and in an individual moderately affected with atrial fibrillation, sick sinus syndrome, and premature ventricular contractions (PMID: 34930020). This variant has been identified in 1/251426 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	RCV000766791	SCV002503359	uncertain significance	not provided	2021-07-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001842316	SCV004819873	uncertain significance	Cardiac arrhythmia	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with phenylalanine at codon 848 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). A functional study has shown that this variant causes a reduction in channel peak current density when expressed in HEK293 cells (PMID: 34930020). This variant has been reported in individual(s) suspected of having long QT syndrome (PMID: 19716085, 25904541) and in an individual moderately affected with atrial fibrillation, sick sinus syndrome, and premature ventricular contractions (PMID: 34930020). This variant has been identified in 1/251426 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000183004	SCV005422624	uncertain significance	not specified	2024-10-21	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.2542A>T (p.Ile848Phe) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-06 in 254026 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2542A>T has been reported in the literature in individuals affected with Long QT Syndrome (Kapplinger_2009, Glazer_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in mild loss of function (>70% reduction of normal activity) in an in vitro assay (Glazer_2022). ClinVar contains an entry for this variant (Variation ID: 67740). Based on the evidence outlined above, the variant was classified as uncertain significance.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058509	SCV000090029	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.