ClinVar Miner

Submissions for variant NM_001130438.3(SPTAN1):c.959G>A (p.Arg320His) (rs140076136)

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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 RCV000727121 SCV000705919 uncertain significance not provided 2017-02-02 criteria provided, single submitter clinical testing
GeneDx RCV000727121 SCV000243131 uncertain significance not provided 2012-04-12 criteria provided, single submitter clinical testing p.Arg320His (CGC>CAC): c.959 G>A in exon 8 of the SPTAN1 gene (NM_001130438.1) The Arg320His missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project did not identify Arg320His in approximately 5000 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. Arg320His alters a position that is highly conserved in the alpha-II spectrin protein, and multiple in silico algorithms predict this variant may be damaging to protein structure/function. However, previously reported pathogenic missense mutations in SPTAN1 are located within the last four spectrin repeats that are essential for dimerization (Saitsu et al., 2010), and the Arg320 residue is outside this region. Additionally, the amino acid substitution is conservative, as Arginine and Histidine are both positively charged amino acids. Therefore, based on the currently available information it is unclear whether Arg320His is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s).
Invitae RCV000636326 SCV000757765 uncertain significance Early infantile epileptic encephalopathy 2018-11-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 320 of the SPTAN1 protein (p.Arg320His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs140076136, ExAC 0.004%). This variant has not been reported in the literature in individuals with SPTAN1-related disease. ClinVar contains an entry for this variant (Variation ID: 207315). 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 C0"). 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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