NM_005097.4:c.406C>T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_005097.4(LGI1):c.406C>T(p.Arg136Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_005097.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LGI1 | NM_005097.4 | c.406C>T | p.Arg136Trp | missense_variant | Exon 4 of 8 | ENST00000371418.9 | NP_005088.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152162Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460858Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1AN XY: 726812
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74322
ClinVar
Submissions by phenotype
Autosomal dominant epilepsy with auditory features Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 136 of the LGI1 protein (p.Arg136Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of lateral temporal lobe epilepsy (PMID: 17562837, 21504429). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5438). 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. Experimental studies have shown that this missense change affects LGI1 function (PMID: 25485908). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
p.Arg136Trp (CGG>TGG): c.406 C>T in exon 4 of the LGI1 gene (NM_005097.2). The R136W missense mutation in the LGI1 gene has been reported previously in an individual with autosomal dominant partial epilepsy with auditory features (ADPEAF) (Michelucci et al., 2007). It was also reported in another family with ADPEAF; however only three out of nine individuals with the mutation had seizures, suggesting reduced penetrance associated with this mutation (Di Bonaventura et al., 2011). Functional studies demonstrate that R136W damages normal protein secretion (Di Bonaventura et al., 2011; Nobile et al., 2009). The R136W mutation 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 is a non-conservative substitution at a position that is conserved through mammals. Therefore, based on currently available information, R136W is considered a disease-causing mutation, and its presence is consistent with a diagnosis of an LGI1-related disorder. This variant has been observed de novo without verified parentage. The variant is found in EPILEPSYV2-1 panel(s). -
LGI1-related disorder Pathogenic:1
The LGI1 c.406C>T variant is predicted to result in the amino acid substitution p.Arg136Trp. This variant has been reported as arising de novo in individuals with epilepsy (Michelucci et al. 2007. PubMed ID: 17562837; Di Bonaventura et al. 2011. PubMed ID: 21504429; Table e1 in Bennett et al. 2017. PubMed ID: 28717674). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -
Epilepsy, familial temporal lobe, 1 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at