Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002003817 | SCV002268721 | likely benign | Early infantile epileptic encephalopathy with suppression bursts | 2022-08-31 | criteria provided, single submitter | clinical testing | |
| Lifecell International Pvt. |
RCV003126073 | SCV003804169 | uncertain significance | Developmental and epileptic encephalopathy 6B | criteria provided, single submitter | clinical testing | The missense variant NM_001165963.4(SCN1A):c.1982C>T (p.Thr661Ile) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Thr661Ile variant is observed in 1/30,612 (0.0033%) alleles from individuals of gnomAD South Asian background in gnomAD. The p.Thr661Ile variant is novel (not in any individuals) in 1kG. There is a moderate physicochemical difference between threonine and isoleucine. The gene SCN1A has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 5.22. 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 0.43 and 1.13, 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. The gene SCN1A contains 537 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. The p.Thr661Ile missense variant is predicted to be damaging by both SIFT and PolyPhen2. The threonine residue at codon 661 of SCN1A is conserved in all mammalian species. The nucleotide c.1982 in SCN1A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. |