ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5958C>A (p.Asn1986Lys) (rs199473335)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
CSER_CC_NCGL; University of Washington Medical Center RCV000148858 SCV000190602 uncertain significance Atrial fibrillation 2014-06-01 no assertion criteria provided research
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.
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 2018-08-21 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 1987 of the SCN5A protein (p.Asn1987Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is present in population databases (rs199473335, ExAC 0.002%). This variant has been observed in a two related individuals affected with atrial fibrillation (PMID: 18088563). This variant is also known as p.N1986K in the literature. ClinVar contains an entry for this variant (Variation ID: 30045). Experimental studies in vitro have shown that this missense change shifts the steady-state activation of the SCN5A channel, but the clinical significance of this observation is uncertain (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.
Laboratory for Molecular Medicine,Partners HealthCare 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.
OMIM RCV000022947 SCV000044238 pathogenic Atrial fibrillation, familial, 10 2008-01-01 no assertion criteria provided literature only

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