ClinVar Miner

Submissions for variant NM_006920.6(SCN1A):c.5764del (p.Arg1922fs) (rs587780446)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520766 SCV000618750 uncertain significance not provided 2017-07-19 criteria provided, single submitter clinical testing The c.5797delC variant in the SCN1A gene has not been published previously as a pathogenic variant nor as a benign variant, to our knowledge. It is reported in ClinVar with conflicting classifications (variant of uncertain significance and pathogenic variant) by other clinical laboratories (SCV000152597.1 and SCV000548753.1; Landrum et al., 2016). This variant causes a frameshift in the C-terminus of the protein, starting with codon Arginine 1933, changes this amino acid to a Glutamine residue, and creates a premature Stop codon at position 3 of the new reading frame, denoted p.Arg1933GlufsX3. It is predicted to result in protein truncation, as the last 77 amino acids are lost and replaced with 2 incorrect amino acids. The c.5797delC variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Genetic Services Laboratory, University of Chicago RCV000118238 SCV000152597 pathogenic Generalized epilepsy with febrile seizures plus, type 2 2013-03-28 criteria provided, single submitter clinical testing
Invitae RCV000469582 SCV000548753 uncertain significance Early infantile epileptic encephalopathy 2017-02-24 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 26 of the SCN1A mRNA (c.5797delC), causing a frameshift at codon 1933. This creates a premature translational stop signal in the last exon of the SCN1A mRNA (p.Arg1933Glufs*3). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt 4 and delete the last 73 amino acids of the SCN1A protein. This variant is not present in population databases (rs587780446, ExAC no frequency) and has not been reported in the literature in individuals with an SCN1A-related disease. ClinVar contains an entry for this variant (Variation ID: 130208). Experimental studies have not been reported for this truncating variant and it is currently unknown if the last 77 amino acids of the SCN1A protein are critical for its function. In summary, this is a rare frameshift variant with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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