ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.86_87invCA (p.Ala29Val)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000249341 SCV000320685 uncertain significance Cardiovascular phenotype 2015-12-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence
GeneDx RCV000183144 SCV000235560 uncertain significance not specified 2017-07-12 criteria provided, single submitter clinical testing The c.86_87delCAinsTG variant in the SCN5A gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge, but has been reported in other individuals tested for arrhythmia at GeneDx. A nucleotide substitution (c.86 C>T) which results in the same amino acid substitution, A29V, has been reported in a patient with presyncope and a QTc of 490ms, who also harbored a pathogenic variant in the KCNQ1 gene (Stattin E et al., 2012). Missense variants in nearby residues (R27H, E30G) have been reported in association with arrhythmia (Stenson P et al., 2014), supporting the functional importance of this region of the protein. Additionally, the A29V variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, A29V results in a conservative amino acid substitution of one non-polar residue for another, and Valine is present at this position in Orangutan. Moreover, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000233493 SCV000291838 uncertain significance Brugada syndrome 2016-02-15 criteria provided, single submitter clinical testing This variant, c.86_87invCA, is a complex sequence change that results in the inversion of two nucleotides in the SCN5A protein that leads to a protein change but does not disrupt the reading frame (p.Ala29Asp). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SCN5A-related disease. ClinVar contains an entry for this variant (Variation ID: 201552). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class 65"). In summary, this is a novel change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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