ClinVar Miner

Submissions for variant NM_006920.6(SCN1A):c.3523G>T (p.Val1175Leu) (rs780607306)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188921 SCV000242551 uncertain significance not provided 2017-01-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN1A gene. The V1186L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V1186L variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution alters a position where amino acids with similar properties to Valine are tolerated across species, and is predicted to be within the cytoplasmic loop between 2nd and 3rd homologous domains. However, the V1186L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000636311 SCV000757750 uncertain significance Early infantile epileptic encephalopathy 2018-01-05 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 1186 of the SCN1A protein (p.Val1186Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs780607306, ExAC 0.009%). This variant has not been reported in the literature in individuals with SCN1A-related disease. ClinVar contains an entry for this variant (Variation ID: 206804). 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 cytoplasmic interdomain linker D2-D3 region of the resulting protein (PMID: 25348405, 18804930), but it is unclear how this variant impacts the function of this protein. 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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