ClinVar Miner

Submissions for variant NM_001130438.3(SPTAN1):c.5545C>T (p.Arg1849Trp) (rs148402616)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189551 SCV000243194 uncertain significance not provided 2014-10-24 criteria provided, single submitter clinical testing p.Arg1849Trp (CGG>TGG): c.5545 C>T in exon 43 of the SPTAN1 gene (NM_001130438.2) The R1849W variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R1849W 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 highly conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, previously reported pathogenic mutations in SPTAN1 include in-frame deletions or duplications located within the last four spectrin repeats of the protein which are essential for dimerization (Saitsu et al., 2010), whereas R1849W is a missense change that lies outside of this region. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV000464908 SCV000553140 uncertain significance Early infantile epileptic encephalopathy 2016-10-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1849 of the SPTAN1 protein (p.Arg1849Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs148402616, ExAC 0.02%) but has not been reported in the literature in individuals with a SPTAN1-related disease. ClinVar contains an entry for this variant (Variation ID: 207376). 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 summary, this variant is a rare missense change with uncertain impact on 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.

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