ClinVar Miner

Submissions for variant NM_001165963.1(SCN1A):c.2729A>G (p.Gln910Arg) (rs1064795735)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487225 SCV000571824 likely pathogenic not provided 2018-05-29 criteria provided, single submitter clinical testing The Q901R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Q910R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Q910R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Additionally, this substitution alters a conserved position predicted to be within the transmembrane segment S5 of the second homologous domain. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants at the same position (Q910K) and in a nearby residue (V907F) have been reported in the Human Gene Mutation Database in association with SCN1A-related disorders (Stenson et al., 2014). Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000636316 SCV000757755 uncertain significance Early infantile epileptic encephalopathy 2017-09-22 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 910 of the SCN1A protein (p.Gln910Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SCN1A-related disease. 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 and their clinical significance is uncertain. This variant identified in the SCN1A gene is located in the transmembrane spanning D2-S5 region of the resulting protein (PMID: 25348405, 18804930), but it is unclear how this variant impacts the function of this protein. A different missense substitution at this codon (p.Gln910Leu) has been determined to be pathogenic (PMID: 28012175). This suggests that the glutamine residue is critical for SCN1A protein function and that other missense substitutions at this position may also be pathogenic. 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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