rs119488099
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Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_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
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
LGI1
NM_005097.4 missense
NM_005097.4 missense
Scores
12
3
4
Clinical Significance
Conservation
PhyloP100: 2.32
Genes affected
LGI1 (HGNC:6572): (leucine rich glioma inactivated 1) This gene encodes a member of the secreted leucine-rich repeat (LRR) superfamily and shares homology with members of the SLIT protein family. The encoded protein may regulate the activity of voltage-gated potassium channels and may be involved in neuronal growth regulation and cell survival. This gene is rearranged as a result of translocations in glioblastoma cell lines, and it is frequently down-regulated or rearranged in malignant gliomas. Mutations in this gene result in autosomal dominant lateral temporal epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LGI1. . Gene score misZ 2.7809 (greater than the threshold 3.09). Trascript score misZ 3.4769 (greater than threshold 3.09). GenCC has associacion of gene with epilepsy, familial temporal lobe, 1, autosomal dominant epilepsy with auditory features.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.908
PP5
Variant 10-93777592-C-T is Pathogenic according to our data. Variant chr10-93777592-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LGI1 | NM_005097.4 | c.406C>T | p.Arg136Trp | missense_variant | 4/8 | ENST00000371418.9 | NP_005088.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LGI1 | ENST00000371418.9 | c.406C>T | p.Arg136Trp | missense_variant | 4/8 | 1 | NM_005097.4 | ENSP00000360472.4 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152162Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460858Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1AN XY: 726812
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74322
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal dominant epilepsy with auditory features Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 06, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect LGI1 protein function (PMID: 25485908). This variant 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). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 136 of the LGI1 protein (p.Arg136Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 12, 2015 | 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
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 09, 2022 | 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
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 12, 2007 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.;.;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;.;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.;.;L
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;.;.;D
REVEL
Uncertain
Sift
Pathogenic
D;.;.;.;D
Sift4G
Pathogenic
D;D;D;.;D
Polyphen
D;.;.;.;D
Vest4
MutPred
Loss of methylation at R136 (P = 0.0274);.;Loss of methylation at R136 (P = 0.0274);Loss of methylation at R136 (P = 0.0274);Loss of methylation at R136 (P = 0.0274);
MVP
MPC
ClinPred
D
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at