rs104894166

chr10-93758280-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_005097.4(LGI1):c.136T>C(p.Cys46Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LGI1 NM_005097.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.03

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, LGI1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 10-93758280-T-C is Pathogenic according to our data. Variant chr10-93758280-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 5433.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LGI1	NM_005097.4	c.136T>C	p.Cys46Arg	missense_variant	1/8	ENST00000371418.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LGI1	ENST00000371418.9	c.136T>C	p.Cys46Arg	missense_variant	1/8	1	NM_005097.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00152 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy, familial temporal lobe, 1 Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2003	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Autosomal dominant epilepsy with auditory features Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 28, 2022

Experimental studies have shown that this missense change affects LGI1 function (PMID: 17067999, 25485908). For these reasons, this variant has been classified as Pathogenic. 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: 5433). This missense change has been observed in individual(s) with autosomal dominant lateral temporal lobe epilepsy (PMID: 12205652). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 46 of the LGI1 protein (p.Cys46Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;.;.;T;T;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D;D;.;.;D;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.9	M;.;.;.;M;.;.;M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-9.1	D;.;.;.;.;.;.;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;.;D;D
Polyphen		1.0	D;.;.;.;D;.;.;D
Vest4		0.97
MutPred		0.97		Gain of disorder (P = 0.0376);Gain of disorder (P = 0.0376);Gain of disorder (P = 0.0376);Gain of disorder (P = 0.0376);Gain of disorder (P = 0.0376);Gain of disorder (P = 0.0376);Gain of disorder (P = 0.0376);Gain of disorder (P = 0.0376);
MVP		0.96
MPC		2.3
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.98
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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

Other links and lift over

dbSNP: rs104894166; hg19: chr10-95518037;