ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.871A>C (p.Asn291His) (rs36210420)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058854 SCV000090374 not provided Torsades de pointes no assertion provided literature only This variant has been reported as associated with torsades de pointes in the following publications (PMID:17161064). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneDx RCV000182950 SCV000235347 uncertain significance not provided 2017-07-13 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN5A gene. The N291H variant has previously been reported as a polymorphism" in an individual of European ancestry with torsades de pointes (Mank-Seymour et al., 2006). In addition, this variant has been observed in other unrelated individuals referred for cardiac genetic testing at GeneDx; however, segregation data is insufficient to determine the pathogenicity of this variant. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Nevertheless, the N291H 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. Furthermore, the N291H variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign."
Invitae RCV000227263 SCV000291839 uncertain significance Brugada syndrome 2017-02-24 criteria provided, single submitter clinical testing This sequence change replaces asparagine with histidine at codon 291 of the SCN5A protein (p.Asn291His). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and histidine. This variant is not present in population databases (rs36210420, ExAC no frequency). This variant has been reported in an individual affected with torsades de pointes. Currently there is insufficient evidence to conclude whether this variant segregates with disease or not (PMID: 17161064). ClinVar contains an entry for this variant (Variation ID: 68051). This variant identified in the SCN5A gene is located in the transmembrane spanning DI-S5/S6 region of the resulting protein (PMID: 25348405). For more information about the location of this variant, please visit www.invitae.com/SCN5A-topology. It is unclear how this variant impacts the function of this protein. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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