ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1340C>G (p.Ala447Gly) (rs199473113)

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Total submissions: 4
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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 RCV000058416 SCV000089936 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:19841300;PMID:20129283).
GeneDx RCV000058416 SCV000235366 uncertain significance not provided 2018-09-07 criteria provided, single submitter clinical testing The A447G variant in the SCN5A gene has not been published in association with a cardiogenetic disorder, but has been reported in one African American control sample (Ackerman et al., 2004; Kapa et al., 2009; Kapplinger et al., 2010). Additionally, the A447G variant is observed in 17/23,260 alleles (0.07%) from individuals of African ancestry in large population cohorts (Lek et al., 2016). The A447G variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.
Invitae RCV000525819 SCV000637077 uncertain significance Brugada syndrome 2018-06-29 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 447 of the SCN5A protein (p.Ala447Gly). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and glycine. This variant is present in population databases (rs199473113, ExAC 0.09%). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions.  ClinVar contains an entry for this variant (Variation ID: 67657). 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). 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 RCV000155813 SCV000205524 uncertain significance not specified 2018-04-10 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory

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