Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics | RCV000518289 | SCV000615023 | uncertain significance | not specified | 2016-10-13 | criteria provided, single submitter | clinical testing | |
| Ce |
RCV000762059 | SCV000892310 | uncertain significance | not provided | 2019-08-01 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV000764288 | SCV000895307 | uncertain significance | Migraine, familial hemiplegic, 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000815244 | SCV000955693 | uncertain significance | Early infantile epileptic encephalopathy with suppression bursts | 2025-01-17 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 46 of the SCN1A protein (p.Glu46Lys). This variant is present in population databases (rs769582667, gnomAD 0.02%). This missense change has been observed in individual(s) with seizures (PMID: 37209046; internal data). ClinVar contains an entry for this variant (Variation ID: 448247). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN1A protein function. 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. |
| Lifecell International Pvt. |
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. |