ClinVar Miner

Submissions for variant NM_001130438.3(SPTAN1):c.131A>G (p.Tyr44Cys) (rs368482631)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724442 SCV000227206 uncertain significance not provided 2015-01-22 criteria provided, single submitter clinical testing
GeneDx RCV000724442 SCV000492109 uncertain significance not provided 2016-11-22 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SPTAN1 gene. The Y44C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Y44C variant is observed in 0.01% alleles from individuals of European background, (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y44C 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 conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, previously reported pathogenic variants 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), and the Y44C residue is outside this region. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000805848 SCV000945821 uncertain significance Early infantile epileptic encephalopathy 2018-09-07 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 44 of the SPTAN1 protein (p.Tyr44Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs368482631, ExAC 0.002%). This variant has not been reported in the literature in individuals with SPTAN1-related disease. ClinVar contains an entry for this variant (Variation ID: 195127). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C25"). 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.

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