Submissions for variant NM_000335.5(SCN5A):c.5958C>A (p.Asn1986Lys)

gnomAD frequency: 0.00004  dbSNP: rs199473335

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154830	SCV000204512	uncertain significance	not specified	2014-03-14	criteria provided, single submitter	clinical testing	The Asn1987Lys variant in SCN5A has been reported in 1 individual with atrial fi brillation and was found to segregate with disease in 1 affected relative (Ellin or 2008). This variant has also been identified in 1/8344 European American chro mosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/ ; dbSNP rs199473335). Functional studies suggest this variant impact the protein (Ellinor 2008), though these in vitro studies may not accurately represent biol ogical function. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, add itional data is needed to fully assess the clinical significance of the Asn1987L ys variant.
GeneDx	RCV000756620	SCV000617271	uncertain significance	not provided	2017-07-05	criteria provided, single submitter	clinical testing	The N1987K variant in the SCN5A gene has been reported previously (as N1986K using alternate nomenclature) in a father and son with atrial fibrillation (Ellinor et al., 2008). Additionally, expression of N1986K in Xenopus oocytes revealed a hyperpolarizing shift in channel steady-state inactivation (Ellinor et al., 2008). The N1987K variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N1987K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret N1987K as a variant of uncertain significance
Invitae	RCV000688881	SCV000816508	uncertain significance	Brugada syndrome	2022-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1987 of the SCN5A protein (p.Asn1987Lys). This variant is present in population databases (rs199473335, gnomAD 0.003%). This missense change has been observed in individual(s) with atrial fibrillation, dilated cardiomyopathy, and/or hypertrophic cardiomyopathy (PMID: 18088563, 30847666). This variant is also known as N1986K. ClinVar contains an entry for this variant (Variation ID: 30045). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects SCN5A function (PMID: 18088563). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756620	SCV000884488	uncertain significance	not provided	2018-02-23	criteria provided, single submitter	clinical testing	The SCN5A c.5961C>A; p.Asn1987Lys was found in the heterozygous state in a father/son pair who were diagnosed with atrial fibrillation with sick sinus syndrome and lone atrial fibrillation, respectively (Ellinor 2008). Functional studies showed that Xenopus oocytes expressing this variant protein exhibited a hyperpolarizing shift in sodium channel steady-state inactivation, but normal voltage-dependent activation and time course of recovery from inactivation (Ellinor 2008). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.001% (identified on 3 out of 254,540 chromosomes), and is classified as a variant of unknown significance in ClinVar (ID: 30045). The asparagine at position 1987 is highly conserved, considering 9 species, and computational analyses of the effects of the p.Asn1987Lys variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, PolyPhen-2: benign). Based on the available information, the clinical significance of the p.Asn1987Lys variant cannot be determined.
Color Diagnostics, LLC DBA Color Health	RCV001841252	SCV001341931	uncertain significance	Cardiac arrhythmia	2022-12-03	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with lysine at codon 1987 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/258138 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.
OMIM	RCV000022947	SCV000044238	pathogenic	Atrial fibrillation, familial, 10	2008-01-01	no assertion criteria provided	literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000148858	SCV000090338	not provided	Atrial fibrillation		no assertion provided	literature only	This variant has been reported as associated with Atrial fibrillation in the following publications (PMID:18088563). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER _CC_NCGL, University of Washington	RCV000148858	SCV000190602	uncertain significance	Atrial fibrillation	2014-06-01	no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV000756620	SCV001921350	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000756620	SCV001930980	uncertain significance	not provided		no assertion criteria provided	clinical testing