Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000413641 | SCV000491521 | likely pathogenic | not provided | 2016-06-21 | criteria provided, single submitter | clinical testing | The L981I variant in the SCN1A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L981I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs within the transmembrane segment S6 of the second homologous domain at a position that is conserved across species. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (M976I, V977M, G979E, G979R, V982L, V983A, N985I, L986P, L986F) have been reported in the Human Gene Mutation Database in association with SCN1A-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The L981I variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000413641 | SCV000697755 | uncertain significance | not provided | 2016-01-01 | criteria provided, single submitter | clinical testing | Variant summary: This c.2941C>A variant affects a conserved nucleotide, resulting in conservative amino acid change from Leu to Ile. 4/5 in-silico tools predict this variant to be damaging. This variant was not found in approximately 121410 chromosomes from broad and large populations from ExAC. To our knowledge, the variant has not been reported in affected individuals via publications and/or reputable databases/clinical laboratories, nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant has currently been classified as a variant of uncertain significance (VUS) until additional information becomes available. |