rs119488099

Variant names:

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

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LGI1
NM_005097.4 missense

Scores

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]

LGI1 links:

ENSG00000280485 (HGNC:):

ENSG00000280485 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 rank	MANE	Protein	UniProt
LGI1	NM_005097.4 link	c.406C>T	p.Arg136Trp	missense_variant	Exon 4 of 8	ENST00000371418.9	NP_005088.1	O95970-1A0A0S2Z4S7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LGI1	ENST00000371418.9 link	c.406C>T	p.Arg136Trp	missense_variant	Exon 4 of 8	1	NM_005097.4	ENSP00000360472.4		O95970-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152162

Hom.:

Cov.:

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:

AN:

1460858

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

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:

AN:

152162

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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

Feb 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 09, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 12, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.52

D;.;.;T;.

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.99

D;D;.;D;D

M_CAP

Benign

0.044

MetaRNN

Pathogenic

0.91

D;D;D;D;D

MetaSVM

Benign

-0.42

MutationAssessor

Benign

1.7

L;.;.;.;L

PrimateAI

Pathogenic

0.81

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over