ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5687G>A (p.Arg1896Gln) (rs761369505)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000622063 SCV000737758 uncertain significance Cardiovascular phenotype 2016-10-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000465773 SCV000545094 uncertain significance Brugada syndrome 2016-10-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1897 of the SCN5A protein (p.Arg1897Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs761369505, ExAC 0.01%). This variant has been reported in an individual affected with long QT syndrome (PMID: 27485560). This variant identified in the SCN5A gene is located in the cytoplasmic C-terminal region of the resulting protein (PMID: 25348405), but it is unclear how this variant impacts the function of this protein. 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. Furthermore, algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function and splicing. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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