rs119488099

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

Scores

12
3
4

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 2.32
Variant links:
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]

Genome browser will be placed here

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
LGI1NM_005097.4 linkuse as main transcriptc.406C>T p.Arg136Trp missense_variant 4/8 ENST00000371418.9 NP_005088.1 O95970-1A0A0S2Z4S7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LGI1ENST00000371418.9 linkuse as main transcriptc.406C>T p.Arg136Trp missense_variant 4/81 NM_005097.4 ENSP00000360472.4 O95970-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152162
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460858
Hom.:
0
Cov.:
29
AF XY:
0.00000138
AC XY:
1
AN XY:
726812
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152162
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 06, 2021For 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 submitterclinical testingGeneDxJan 12, 2015p.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 submitterclinical testingPreventionGenetics, part of Exact SciencesDec 09, 2022The 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 providedliterature onlyOMIMJun 12, 2007- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.71
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.17
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.52
D;.;.;T;.
Eigen
Pathogenic
0.73
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Pathogenic
0.99
D;D;.;D;D
M_CAP
Benign
0.044
D
MetaRNN
Pathogenic
0.91
D;D;D;D;D
MetaSVM
Benign
-0.42
T
MutationAssessor
Benign
1.7
L;.;.;.;L
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-5.8
D;.;.;.;D
REVEL
Uncertain
0.46
Sift
Pathogenic
0.0
D;.;.;.;D
Sift4G
Pathogenic
0.0
D;D;D;.;D
Polyphen
1.0
D;.;.;.;D
Vest4
0.73
MutPred
0.83
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
0.86
MPC
1.8
ClinPred
1.0
D
GERP RS
6.1
Varity_R
0.82
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs119488099; hg19: chr10-95537349; COSMIC: COSV65058073; COSMIC: COSV65058073; API