ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.4279G>T (p.Ala1427Ser) (rs200034939)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183069 SCV000235478 likely pathogenic not provided 2018-03-22 criteria provided, single submitter clinical testing The A1428S variant that is likely pathogenic in the SCN5A gene has been previously reported in association with LQTS (Yoshikane Y et al., 2013). The A1428S mutation was reported in a 7-year-old male with LQTS and seizures, and was maternally inherited in conjunction with a variant in KCNE1. This patient was also reported to have a paternally inherited mutation in the KCNH2 gene. None of this patients relatives were reported to have a long QT interval (Yoshikane Y et al., 2013). The A1428S mutation was also previously reported in another patient with Brugada syndrome, however no population or segregation data were provided (Sommariva E et al., 2013). The A1428S mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, but was identified in 1/552 alleles in individuals of Asian ancestry in the 1000 Genomes Project. The A1428S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Moreover, mutations in this residue (A1428V) and in nearby residues (G1420R, A1427S, D1430N, R1432G, R1432S) have been reported in association with SCN5A-related disorders, further supporting the functional importance of this residue and region of the protein. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded.The variant is found in POSTMORTEM panel(s).
Invitae RCV000199660 SCV000255232 uncertain significance Brugada syndrome 2015-01-29 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 1428 of the SCN5A protein (p.Ala1428Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. This variant has been reported in the literature and is present in population databases (rs200034939, 0.05%). It has been observed in a patient with Brugada syndrome (PMID: 23321620), as well as a patient with long QT syndrome (PMID: 23237912). In addition, a variant in the same codon, p.Ala1428Val, is absent from population databases and was observed in a patient with Brugada syndrome (PMID: 20129283). 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 addition, a paralogue annotation algorithm suggests that the p.Ala1428 residue is important for normal protein function because variants in an analogous position in SCN1A are causative of myoclonic epilepsy. The algorithm has a positive predictive value of 98.7%, but the sensitivity is unknown and the clinical significance of this observation is uncertain (PMID: 24136861). In summary, this is a rare missense change with uncertain impact on protein function. Although this variant has been seen in patients and has some indirect evidence to suggest that it is deleterious, there have not been any functional studies and segregation analysis has not been performed. At this time, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000155812 SCV000205523 uncertain significance not specified 2014-11-06 criteria provided, single submitter clinical testing The p.Ala1428Ser variant in SCN5A has been reported in 1 a 13 year old individua l with Long QT syndrome (likely of Japanese ancestry) and 1 Italian individual w ith Brugada syndrome (Sommariva 2013, Yoshikane 2013). In the family reported by Yoshikane et al. this variant was also present in the reportedly unaffected mot her and aunt, raising the possibility that it has a milder effect or is benign. This variant has been identified in 1/194 Han Chinese chromosomes by the 1000 Ge nomes Project (dbSNP rs200034939) and in 3/8766 East Asian chromosomes by the Ex ome Aggregation Consortium (ExAC; http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that it may impact the prote in, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Ala1428Ser variant is uncertain.

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