ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.4339A>C (p.Ile1447Leu) (rs199473250)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000252530 SCV000320056 uncertain significance Cardiovascular phenotype 2015-08-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (benign),Insufficient or conflicting evidence
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058662 SCV000090182 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Invitae RCV000058662 SCV000819309 uncertain significance Brugada syndrome 2018-10-08 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with leucine at codon 1448 of the SCN5A protein (p.Ile1448Leu). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is present in population databases (rs199473250, ExAC 0.005%). This variant has been observed in an individual referred for testing for Brugada syndrome and in an individual with hypertrophic cardiomyopathy (PMID: 20129283, 25351510). ClinVar contains an entry for this variant (Variation ID: 67882). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000151779 SCV000200229 uncertain significance not specified 2014-11-13 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Ile1448Leu va riant in SCN5A has been reported in 1 individual with Brugada syndrome (Kappling er 2010) and was absent from large population studies. Isoleucine (Ile) at posit ion 1448 is not conserved in mammals or evolutionarily distant species and oposs um, Tasmanian devil, wallaby, and multiple birds and fish species carry a leucin e (Leu) at this position, suggesting that this change may be tolerated. Addition al computational prediction tools suggest that this variant may not impact the p rotein, though this information is not predictive enough to rule out pathogenici ty. In summary, while the clinical significance of the p.Ile1448Leu variant is u ncertain, the presence of the variant amino acid in multiple other species, incl uding mammals, suggests that it is more likely to be benign.

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