Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Lifecell International Pvt. |
RCV001537935 | SCV001754760 | uncertain significance | Severe myoclonic epilepsy in infancy | criteria provided, single submitter | clinical testing | A heterozygous missense variant (c.5783G>A) in exon 29 of the SCN1A gene that results in the amino acid substitution from Arginine to Histidine at codon 1928 (p.Arg1928His) was identified. The observed variant is not present in both the 1000 Genomes and gnomAD databases. The reference base is conserved across the mammals and in-silico predictions by Polyphen and SIFT are damaging. The Missense Variants Z-Score for this variant is 5.23. 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 Missense Badness Score and MPC value for this variant are 0.58 and 0.89, respectively. Missense Badness Score is the normalized fold difference of missense substitutions between observed and expected variants from ExAC dataset. 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 variants is deleterious. Variants with MPC ≥ 2 have a rate nearly 6 times higher in cases than in controls. While those with intermediate MPC values (1 ≤ MPC < 2) have a more modest excess in cases. Based on the above evidence this variant has been classified as Variant of uncertain significance according to the ACMG guidelines. | |
| Invitae | RCV002568236 | SCV003483052 | uncertain significance | Early infantile epileptic encephalopathy with suppression bursts | 2023-10-17 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1928 of the SCN1A protein (p.Arg1928His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1180554). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt 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. |