NM_005097.4:c.600C>A

Variant names:

• chr10-93792839-C-A
• rs148862146
• NM_005097.4:c.600C>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005097.4(LGI1):​c.600C>A​(p.Cys200*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 (★). Synonymous variant affecting the same amino acid position (i.e. C200C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LGI1 NM_005097.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.129
• 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)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-93792839-C-A is Pathogenic according to our data. Variant chr10-93792839-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2756254.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LGI1	NM_005097.4	c.600C>A	p.Cys200*	stop_gained	Exon 6 of 8	ENST00000371418.9	NP_005088.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LGI1	ENST00000371418.9	c.600C>A	p.Cys200*	stop_gained	Exon 6 of 8	1	NM_005097.4	ENSP00000360472.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant epilepsy with auditory features Pathogenic:1

Aug 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with LGI1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys200*) in the LGI1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LGI1 are known to be pathogenic (PMID: 24206907). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	21
DANN	Uncertain	0.98
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.62	D
PhyloP100		-0.13
Vest4		0.97
GERP RS		-11
Mutation Taster		=6/194	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148862146; hg19: chr10-95552596;