Submissions for variant NM_000335.5(SCN5A):c.5857G>A (p.Glu1953Lys)

gnomAD frequency: 0.00013  dbSNP: rs397517956

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041633	SCV000065329	uncertain significance	not specified	2012-09-28	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Glu1954Lys vari ant in SCN5A has not been reported in the literature nor previously identified b y our laboratory. The affected amino acid (glutamic acid, Glu) is poorly conser ved in evolution with at least one mammalian species carrying the variant amino acid. This suggests but does not prove that this change is tolerated. Addition al studies are needed to fully assess its clinical significance.
GeneDx	RCV000713148	SCV000235549	uncertain significance	not provided	2019-10-30	criteria provided, single submitter	clinical testing	Reported in conjunction with a pathogenic variant in KCNQ1 in a child with LQTS (Lieve et al., 2013); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 48312; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23631430, 30847666)
Invitae	RCV000713148	SCV000291826	uncertain significance	not provided	2024-01-31	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 1954 of the SCN5A protein (p.Glu1954Lys). This variant is present in population databases (rs397517956, gnomAD 0.04%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 23631430, 29517769, 30847666). ClinVar contains an entry for this variant (Variation ID: 48312). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Ambry Genetics	RCV000241908	SCV000320114	uncertain significance	Cardiovascular phenotype	2022-02-23	criteria provided, single submitter	clinical testing	The p.E1954K variant (also known as c.5860G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 5860. The glutamic acid at codon 1954 is replaced by lysine, an amino acid with similar properties. This variant has been detected in one individual diagnosed with long QT syndrome who was also reported to carry a second alteration in KCNQ1 (p.R539W) (Lieve KV et al., Genet Test Mol Biomarkers 2013 Jul; 17(7):553-61). This alteration was also reported in a pediatric dilated cardiomyopathy (DCM) cohort and a cardiomyopathy/arrhythmia genetic testing cohort; however, clinical details were limited (Herkert JC et al. Genet. Med., 2018 11;20:1374-1386; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Athena Diagnostics Inc	RCV000713148	SCV000843726	uncertain significance	not provided	2018-08-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001841615	SCV001350166	uncertain significance	Cardiac arrhythmia	2023-12-11	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1954 of the SCN5A protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a child affected with long QT syndrome, who also carried a pathogenic variant in the KCNQ1 gene that could explain the observed phenotype (PMID: 23631430). This variant has also been reported in two individuals affected with dilated cardiomyopathy (PMID: 29517769, 30847666). This variant has been identified in 11/277646 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.
PreventionGenetics, part of Exact Sciences	RCV003894874	SCV004717232	uncertain significance	SCN5A-related condition	2024-01-06	criteria provided, single submitter	clinical testing	The SCN5A c.5860G>A variant is predicted to result in the amino acid substitution p.Glu1954Lys. This variant was reported in an individual with long QT syndrome who also had the variant KCNQ1 c.1615C>T (p.Arg539Trp) (Lieve et al. 2013. PubMed ID: 23631430). This variant was also reported in two individuals with dilated cardiomyopathy (Herkert et al. 2018. PubMed ID: 29517769; online supplementary file 2, van Lint et al. 2019. PubMed ID: 30847666). This variant is reported in 0.037% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.