ClinVar Miner

Submissions for variant NM_006920.6(SCN1A):c.4288G>A (p.Ala1430Thr) (rs121917974)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413422 SCV000491509 likely pathogenic not provided 2016-06-22 criteria provided, single submitter clinical testing The A1441T variant in the SCN1A gene has been reported previously in a patient with Dravetsyndrome (Lee et al., 2015). The A1441T variant was not observed in approximately 6500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. The A1441T variant is anon-conservative amino acid substitution, which is likely to impact secondary protein structure asthese residues differ in polarity, charge, size and/or other properties. This substitution occurs at aconserved position within the pore forming loop between the S5 and S6 transmembrane segments ofthe third homologous domain. In silico analysis predicts this variant is probably damaging to theprotein structure/function. The A1441T variant is a strong candidate for a pathogenic variant, however the possibility it may be a rarebenign variant cannot be excluded.
Invitae RCV000692374 SCV000820194 uncertain significance Early infantile epileptic encephalopathy 2018-05-15 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1441 of the SCN1A protein (p.Ala1441Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Dravet syndrome (PMID: 25459968). ClinVar contains an entry for this variant (Variation ID: 372966). 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 extracellular D3-P3 region of the resulting protein (PMID: 25348405, 18804930), it is unclear how this variant impacts the function of this protein.  However, the observation of one or more missense substitutions at this codon (p.Ala1441Pro) in affected individuals suggests that this may be a clinically significant residue (PMID: 17347258, 23895530). 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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