ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1345A>G (p.Thr449Ala) (rs199473571)

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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 RCV000058417 SCV000089937 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:19841300;PMID:20129283).
GeneDx RCV000058417 SCV000620479 uncertain significance not provided 2017-08-31 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN5A gene. The T449A variant has previously been reported in at least one control individual of unknown ethnicity (Kapa et al., 2009; Kapplinger et al., 2010). The T449A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This 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. However, this substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function.
Invitae RCV000462539 SCV000545088 uncertain significance Brugada syndrome 2016-12-30 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 449 of the SCN5A protein (p.Thr449Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs199473571, ExAC 0.03%) and has been reported in the literature in an unaffected control individual (PMID: 25904541). ClinVar contains an entry for this variant (Variation ID: 67658). 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 alanine amino acid residue is also 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000058417 SCV000924954 uncertain significance not provided 2017-01-27 no assertion criteria provided provider interpretation Given the absence of this variant in the literature, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). There is no case data available for this variant. This variant is present in ClinVar. It was submitted by one reviewer, the Cardiovascular Biomedical Research Unit, and no clinical assertions were provided. This variant has been seen in 1 out of 1300 control individuals. This same control population is reported twice (Kapa et al. 2009, Kapplinger et al, 2010 - both from the Ackerman group). "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 threonine at codon 449 is moderately conserved across species. This variant is present in at least 2 individuals from large population databases. Note that the phenotype of the individuals in these datasets is not publicly available. The datasets arecomprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease: -ExAC: This variant is present in 2 out of 47,969 individuals (MAF=0.00021) in the Exome Aggregation Consortium Dataset (ExAC; http://exac.broadinstitute.org/), which currently includes variant calls on >60,000 unrelated individuals of African, Asian, European and Latino descent. Specifically, it is present in 2 out of 3,288 individuals of East Asian descent (MAF=0.03%). -gnomAD: Note: the gnomAD database is in beta mode and therefore we are currently using ExAC for our population count. I am including the data from gnomAD for the purposes of re-review. The variant was reported online in 2 of 123,214 individuals (MAF=0.00081%)) in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 2 of 8,526 individuals of East Asian descent (MAF=0.011%) -This variant has been seen in 1 out of 1300 controls from two papers pertaining to the same cohort (Kapa et al. 2009, Kapplinger et al, 2010 - both from the Ackerman group).

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