Submissions for variant NM_000335.5(SCN5A):c.142G>A (p.Glu48Lys)

gnomAD frequency: 0.00006  dbSNP: rs199473048

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183168	SCV000235584	uncertain significance	not provided	2024-12-11	criteria provided, single submitter	clinical testing	Reported in association with LQTS, alcoholic cardiomyopathy, Brugada syndrome, and sudden infant death (PMID: 25904541, 19716085, 26746457, 28412158, 30086531, 29773157, 31737537); In vitro studies in cultured cells suggest that p.(E48K) functions similar to wild-type channels (PMID: 25904541); 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: 28150151, 26746457, 29773157, 28412158, 30086531, 36693943, 19716085, 25904541, 31737537)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000183168	SCV000760257	uncertain significance	not provided	2024-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 48 of the SCN5A protein (p.Glu48Lys). This variant is present in population databases (rs199473048, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 19716085, 30086531, 31737537). ClinVar contains an entry for this variant (Variation ID: 67663). 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. Experimental studies have shown that this missense change does not substantially affect SCN5A function (PMID: 25904541). 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.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000678959	SCV000805175	uncertain significance	Brugada syndrome 1	2018-05-11	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825449	SCV000966750	uncertain significance	not specified	2018-06-04	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Glu48Lys vari ant in SCN5A has been reported in one individual with LQTS (Kapplinger 2009) and in 16/274964 of total chromosomes by the Genome Aggregation Database (gnomAD, h ttp://gnomad.broadinstitute.org; dbSNP rs199473048). Computational prediction to ols and conservation analysis do not provide strong support for or against an im pact to the protein; however, gorillas carry a lysine (Lys) at this position, ra ising the possibility that this change may be tolerated. In addition, in vitro s tudies suggest that this variant does not impact Nav1.5 channel function; howeve r, these types of assays may not accurately represent biological function (Kappl inger 2015; Anderson 2017). In summary, while the clinical significance of the p.Glu48Lys variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP criteria applied: BS1_supporting.
Color Diagnostics, LLC DBA Color Health	RCV001842282	SCV001341929	uncertain significance	Cardiac arrhythmia	2023-12-02	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 48 of the SCN5A protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. This variant is found within a highly conserved N-terminus domain (a.a. 1-131). 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 two individuals suspected of being affected with Brugada syndrome (PMID: 31737537) and in an individual affected with sudden infant death (PMID: 30086531). This variant has been identified in 17/278150 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.
Genetics and Genomics Program, Sidra Medicine	RCV001293135	SCV001434125	uncertain significance	Primary dilated cardiomyopathy		criteria provided, single submitter	research
All of Us Research Program, National Institutes of Health	RCV001842282	SCV004819128	uncertain significance	Cardiac arrhythmia	2024-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 48 of the SCN5A protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. This variant is found within a highly conserved N-terminus domain (a.a. 1-131). 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 two individuals suspected of being affected with Brugada syndrome (PMID: 31737537) and in an individual affected with sudden infant death (PMID: 30086531). This variant has been identified in 17/278150 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	RCV004019033	SCV004943815	uncertain significance	Cardiovascular phenotype	2021-02-26	criteria provided, single submitter	clinical testing	The c.142G>A (p.E48K) alteration is located in exon 2 (coding exon 1) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 142, causing the glutamic acid (E) at amino acid position 48 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058423	SCV000089943	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.