ClinVar Genomic variation as it relates to human health

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.

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.

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.

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.

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.

The c.5961C>A (p.N1987K) alteration is located in exon 28 (coding exon 27) of the SCN5A gene. This alteration results from a C to A substitution at nucleotide position 5961, causing the asparagine (N) at amino acid position 1987 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Reported (as N1986K using alternate nomenclature) in a father and son with atrial fibrillation, and expression in Xenopus oocytes revealed a hyperpolarizing shift in channel steady-state inactivation (PMID: 18088563); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22581653, 25637381, 18088563, 30847666)

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.