ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.3176A>T (p.Asp1059Val) (rs779306054)

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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 RCV000724139 SCV000226450 uncertain significance not provided 2014-09-13 criteria provided, single submitter clinical testing
GeneDx RCV000724139 SCV000621716 uncertain significance not provided 2017-10-19 criteria provided, single submitter clinical testing The D1059V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is observed in 10/18814 (0.05%) alleles from individuals of East Asianbackground, in large population cohorts (Lek et al., 2016). The D1059V 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. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position that is not conserved that is predicted to be in the cytoplasmic loop between the second and third homologous domains. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000795103 SCV000934545 uncertain significance Early infantile epileptic encephalopathy 2018-08-06 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 1059 of the SCN1A protein (p.Asp1059Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is present in population databases (rs779306054, ExAC 0.04%). This variant has not been reported in the literature in individuals with SCN1A-related disease. ClinVar contains an entry for this variant (Variation ID: 194616). 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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