NM_005097.4:c.56T>C

Variant names:

• chr10-93758200-T-C
• rs1589746991
• NM_005097.4:c.56T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005097.4(LGI1):​c.56T>C​(p.Ile19Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I19V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LGI1 NM_005097.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.78
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant epilepsy with auditory features

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• epilepsy, familial temporal lobe, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000303320 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31794232).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LGI1	NM_005097.4	c.56T>C	p.Ile19Thr	missense_variant	Exon 1 of 8	ENST00000371418.9	NP_005088.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LGI1	ENST00000371418.9	c.56T>C	p.Ile19Thr	missense_variant	Exon 1 of 8	1	NM_005097.4	ENSP00000360472.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant epilepsy with auditory features Uncertain:1

Feb 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 19 of the LGI1 protein (p.Ile19Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LGI1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Jul 11, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	20
DANN	Benign	0.86
DEOGEN2	Benign	0.21	T;.;.;.;.;T;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.026
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.94	D;D;.;.;D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.32	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.1	L;.;.;.;L;.;.;L
PhyloP100		3.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.36	N;.;.;.;.;.;.;N
REVEL	Uncertain	0.35
Sift	Benign	0.46	T;.;.;.;.;.;.;T
Sift4G	Benign	0.51	T;T;T;T;T;.;T;T
Polyphen		0.18	B;.;.;.;B;.;.;P
Vest4		0.52
MutPred		0.57		Loss of stability (P = 0.0161);Loss of stability (P = 0.0161);Loss of stability (P = 0.0161);Loss of stability (P = 0.0161);Loss of stability (P = 0.0161);Loss of stability (P = 0.0161);Loss of stability (P = 0.0161);Loss of stability (P = 0.0161);
MVP		0.92
MPC		1.0
ClinPred		0.52	D
GERP RS		4.7
PromoterAI		0.012	Neutral
Varity_R		0.087
gMVP		0.38
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1589746991; hg19: chr10-95517957;