Submissions for variant NM_005097.4(LGI1):c.1421G>A (p.Arg474Gln)

dbSNP: rs1064794249

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485877	SCV000568383	likely pathogenic	not provided	2017-03-14	criteria provided, single submitter	clinical testing	The R474Q variant in the LGI1 gene has been reported previously in a family with multiple affected relatives who had features consistent with autosomal dominant lateral temporal lobe epilepsy (Kawamata et al., 2010). Functional studies the of R474Q variant indicate it does not inhibit protein secretion, but does impair interaction of the LGI1 protein with specific receptors on the cell surface (Dazzo et al., 2016). The R474Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R474Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Further, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R474Q as a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003595993	SCV004295662	likely pathogenic	Autosomal dominant epilepsy with auditory features	2023-07-07	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects LGI1 function (PMID: 27760137, 29670100). 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) has been performed at Invitae 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 LGI1 protein function. ClinVar contains an entry for this variant (Variation ID: 420035). This missense change has been observed in individuals with autosomal dominant lateral temporal lobe epilepsy (PMID: 19780791; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 474 of the LGI1 protein (p.Arg474Gln).