NM_001042492.3(NF1):c.2999G>T (p.Arg1000Leu) AND Neurofibromatosis, type 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 31, 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:: RCV000706070.7

Allele description [Variation Report for NM_001042492.3(NF1):c.2999G>T (p.Arg1000Leu)]

NM_001042492.3(NF1):c.2999G>T (p.Arg1000Leu)

Gene:

NF1:neurofibromin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q11.2

Genomic location:

Preferred name:

NM_001042492.3(NF1):c.2999G>T (p.Arg1000Leu)

HGVS:

NC_000017.11:g.31230268G>T
NG_009018.1:g.140292G>T
NM_000267.3:c.2999G>T
NM_001042492.3:c.2999G>TMANE SELECT
NP_000258.1:p.Arg1000Leu
NP_001035957.1:p.Arg1000Leu
NP_001035957.1:p.Arg1000Leu
LRG_214t1:c.2999G>T
LRG_214t2:c.2999G>T
LRG_214:g.140292G>T
LRG_214p1:p.Arg1000Leu
LRG_214p2:p.Arg1000Leu
NC_000017.10:g.29557286G>T
NM_001042492.2:c.2999G>T
NM_001042492.3:c.2999G>T
p.R1000L

Protein change:

R1000L

Links:

dbSNP: rs753082620

NCBI 1000 Genomes Browser:

rs753082620

Molecular consequence:

NM_000267.3:c.2999G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001042492.3:c.2999G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Neurofibromatosis, type 1 (NF1)
Synonyms:: NEUROFIBROMATOSIS, TYPE I; Recklinghausen's disease; Von Recklinghausen disease; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0018975; MedGen: C0027831; Orphanet: 636; OMIM: 162200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000835101	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 31, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25074460, 27838393, 34080803, 28492532
SCV002560251	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 15, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000835101

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 31, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002560251

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 15, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Neurofibromatosis type 1 molecular diagnosis: what can NGS do for you when you have a large gene with loss of function mutations?

Pasmant E, Parfait B, Luscan A, Goussard P, Briand-Suleau A, Laurendeau I, Fouveaut C, Leroy C, Montadert A, Wolkenstein P, Vidaud M, Vidaud D.

Eur J Hum Genet. 2015 May;23(5):596-601. doi: 10.1038/ejhg.2014.145. Epub 2014 Jul 30.

PubMed [citation]

PMID:: 25074460
PMCID:: PMC4402624

Mutation spectrum of NF1 gene in Italian patients with neurofibromatosis type 1 using Ion Torrent PGM™ platform.

Calì F, Chiavetta V, Ruggeri G, Piccione M, Selicorni A, Palazzo D, Bonsignore M, Cereda A, Elia M, Failla P, Figura MG, Fiumara A, Maitz S, Luana Mandarà GM, Mattina T, Ragalmuto A, Romano C, Ruggieri M, Salluzzo R, Saporoso A, Schepis C, Sorge G, et al.

Eur J Med Genet. 2017 Feb;60(2):93-99. doi: 10.1016/j.ejmg.2016.11.001. Epub 2016 Nov 9.

PubMed [citation]

PMID:: 27838393

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000835101.5

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

Description

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. This variant disrupts the p.Arg1000 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25074460, 27838393, 34080803). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) performed at Invitae indicates that this missense variant is expected to disrupt NF1 protein function. ClinVar contains an entry for this variant (Variation ID: 186250). This variant has not been reported in the literature in individuals affected with NF1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1000 of the NF1 protein (p.Arg1000Leu).

#	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 Genome-Nilou Lab, SCV002560251.1

#	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	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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