Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000189005 | SCV000242636 | uncertain significance | not provided | 2017-12-01 | criteria provided, single submitter | clinical testing | p.Ala1834Val (GCG>GTG): c.5501 C>T in exon 26 of the SCN1A gene (NM_001165963.1) The Ala1834Val missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a conservative substitution of one uncharged, non-polar amino acid for another at a position that is conserved in placental mammals but is not conserved in more distantly related species. However, it alters a position between the sixth transmembrane domain and the IQ domain and other missense mutations associated with Dravet syndrome (Phe1831Ser, Ala1832Pro, Leu1835Phe) have been reported in this region of the protein. In silico analysis is inconsistent with regard to the effect this variant may have on the protein structure/function. Therefore, based on the currently available information, it is unclear whether Ala1834Val is a disease-causing mutation or a rare benign variant.The variant is found in INFANT-EPI panel(s). |
Genomic Research Center, |
RCV000714534 | SCV000845231 | uncertain significance | Generalized epilepsy with febrile seizures plus, type 2 | 2018-08-07 | criteria provided, single submitter | clinical testing | |
Genomic Research Center, |
RCV000714535 | SCV000845232 | uncertain significance | Severe myoclonic epilepsy in infancy | 2018-08-07 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000189005 | SCV002496537 | uncertain significance | not provided | 2022-03-01 | criteria provided, single submitter | clinical testing | SCN1A: PP2, PP3 |
Lifecell International Pvt. |
RCV003128153 | SCV003804187 | likely pathogenic | Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2; Developmental and epileptic encephalopathy 6B | criteria provided, single submitter | clinical testing | The missense variant NM_001165963.4 (SCN1A):c.5501C>T (p.Ala1834Val) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ala1834Val variant is observed in 2/30,616 (0.0065%) alleles from individuals of gnomAD South Asian background in gnomAD. The p.Ala1834Val variant is novel (not in any individuals) in 1kG. There is a small physicochemical difference between alanine and valine, which is not likely to impact secondary protein structure as these residues share similar properties. 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 and MPC scores for this variant is 0.35 and 1.56 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. 4 variants within 6 amino acid positions of the variant p.Ala1834Val have been shown to be pathogenic, while none have been shown to be benign. The p.Ala1834Val missense variant is predicted to be damaging by both SIFT and PolyPhen2. The alanine residue at codon 1834 of SCN1A is conserved in all mammalian species. The nucleotide c.5501 in SCN1A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. | |
Revvity Omics, |
RCV000189005 | SCV004237149 | uncertain significance | not provided | 2023-11-19 | criteria provided, single submitter | clinical testing |