ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.136G>A (p.Glu46Lys) (rs769582667)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000518289 SCV000615023 uncertain significance not specified 2016-10-13 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000762059 SCV000892310 uncertain significance not provided 2019-08-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764288 SCV000895307 uncertain significance Familial hemiplegic migraine type 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000815244 SCV000955693 uncertain significance Early infantile epileptic encephalopathy with suppression bursts 2019-08-21 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 46 of the SCN1A protein (p.Glu46Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs769582667, ExAC 0.03%). This variant has not been reported in the literature in individuals with SCN1A-related disease. ClinVar contains an entry for this variant (Variation ID: 440563). 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 C5). 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. 5
LifeCell International Pvt. Ltd RCV001537936 SCV001754812 uncertain significance Generalized epilepsy with febrile seizures plus, type 2 criteria provided, single submitter clinical testing A heterozygous missense variant (c.136G>A) in exon 4 of the SCN1A gene that results in the amino acid substitution from Glutamic acid to Lysine at codon 46 (p.Glu46Lys) was identified. The observed variant has a minor allele frequency of 0.0028% in gnomAD database and not reported in 1000 genome database. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. The Missense Variants Z-Score for this variant is 5.28. Missense Variants Z-Score is produced by the Exome Aggregation Consortium (60,706 adult humans) by computing a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer missense variants than expected. (DOI: 10.1038/nature19057). The MPC score for this variant is 0.98. MPC score is computed on an analysis of the ExAC population frequencies, the Missense Badness Score is the normalized fold difference of observed versus expected missense substitutions in sub-genic regions. This score is then combined with orthogonal deleteriousness metrics into one score called MPC (for Missense badness, PolyPhen-2, and Constraint) designed to classify whether a missense variant is deleterious. (DOI: 10.1101/148353). Based on the above evidence this variant has been classified as variant of uncertain significance according to the ACMG guidelines.

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