NM_001077350.3(NPRL3):c.1270C>T (p.Arg424Ter) AND Epilepsy, familial focal, with variable foci 3

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Dec 17, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000241508.13

Allele description [Variation Report for NM_001077350.3(NPRL3):c.1270C>T (p.Arg424Ter)]

NM_001077350.3(NPRL3):c.1270C>T (p.Arg424Ter)

Genes:

NPRL3:NPR3 like, GATOR1 complex subunit [Gene - OMIM - HGNC]
HBA-LCR:alpha-globin locus control region [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_001077350.3(NPRL3):c.1270C>T (p.Arg424Ter)

HGVS:

NC_000016.10:g.89794G>A
NG_029669.1:g.53906C>T
NG_042799.1:g.2087G>A
NM_001039476.3:c.733C>T
NM_001077350.3:c.1270C>TMANE SELECT
NM_001243247.2:c.1036C>T
NM_001243248.2:c.1195C>T
NM_001243249.2:c.1195C>T
NP_001034565.1:p.Arg245Ter
NP_001070818.1:p.Arg424Ter
NP_001230176.1:p.Arg346Ter
NP_001230177.1:p.Arg399Ter
NP_001230178.1:p.Arg399Ter
NC_000016.9:g.139792G>A
NM_001077350.1:c.1270C>T
NM_001077350.2:c.1270C>T

Protein change:

R245*; ARG424TER

Links:

OMIM: 600928.0004; dbSNP: rs886037961

NCBI 1000 Genomes Browser:

rs886037961

Molecular consequence:

NM_001039476.3:c.733C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001077350.3:c.1270C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001243247.2:c.1036C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001243248.2:c.1195C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001243249.2:c.1195C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Epilepsy, familial focal, with variable foci 3 (FFEVF3)
Identifiers:: MONDO: MONDO:0014925; MedGen: C4310708; OMIM: 617118

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000299385	OMIM	no assertion criteria provided	Pathogenic (Sep 21, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001213929	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 17, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26285051, 26505888, 27173016, 28492532
SCV001994779	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 18, 2021)	maternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004801335	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	maternal	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3.

Sim JC, Scerri T, Fanjul-Fernández M, Riseley JR, Gillies G, Pope K, van Roozendaal H, Heng JI, Mandelstam SA, McGillivray G, MacGregor D, Kannan L, Maixner W, Harvey AS, Amor DJ, Delatycki MB, Crino PB, Bahlo M, Lockhart PJ, Leventer RJ.

Ann Neurol. 2016 Jan;79(1):132-7. doi: 10.1002/ana.24502. Epub 2015 Dec 12.

PubMed [citation]

PMID:: 26285051

Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy.

Ricos MG, Hodgson BL, Pippucci T, Saidin A, Ong YS, Heron SE, Licchetta L, Bisulli F, Bayly MA, Hughes J, Baldassari S, Palombo F; Epilepsy Electroclinical Study Group., Santucci M, Meletti S, Berkovic SF, Rubboli G, Thomas PQ, Scheffer IE, Tinuper P, Geoghegan J, Schreiber AW, et al.

Ann Neurol. 2016 Jan;79(1):120-31. doi: 10.1002/ana.24547. Epub 2015 Dec 12.

PubMed [citation]

PMID:: 26505888

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000299385.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In affected members of a French family (family F) with familial focal epilepsy with variable foci-3 (FFEVF3; 617118), Weckhuysen et al. (2016) identified a heterozygous c.1270C-T transition (c.1270C-T, NM_001077350) in the NPRL3 gene, resulting in an arg424-to-ter (R424X) substitution. The mutation, which was found by sequencing a targeted epilepsy gene panel, was confirmed by Sanger sequencing and filtered against the Exome Variant Server database; it was not found in the ExAC database. At least 1 unaffected family member carried the mutation, consistent with incomplete penetrance. Analysis of patient cells showed that the mutant transcript was subject to nonsense-mediated mRNA decay, consistent with haploinsufficiency. Brain sample from 1 of the patients, who had focal cortical dysplasia, showed hyperactivation of the mTOR pathway in normal and dysmorphic neurons. These findings suggested that the NPRL3 mutation resulted in a loss of function of the GATOR1 complex.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001213929.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Arg424*) in the NPRL3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPRL3 are known to be pathogenic (PMID: 26285051, 26505888). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with focal epilepsy (PMID: 27173016). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 254360). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Equipe Genetique des Anomalies du Developpement, Université de Bourgogne, SCV001994779.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004801335.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The stop gained variant c.1270C>T(p.Arg424Ter) in NPRL3 gene has been reported in heterozygous state in individuals with focal epilepsy (Weckhuysen S, et al., 2016, Abumurad S, et al., 2021). The variant is novel (not in any individuals) in gnomAD Exomes and in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing (Ricos MG, et al., 2016). For these reasons, this variant has been classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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