NM_001042492.3(NF1):c.801G>A (p.Trp267Ter) AND Neurofibromatosis, type 1

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Jul 25, 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:: RCV000699692.18

Allele description [Variation Report for NM_001042492.3(NF1):c.801G>A (p.Trp267Ter)]

NM_001042492.3(NF1):c.801G>A (p.Trp267Ter)

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.801G>A (p.Trp267Ter)

HGVS:

NC_000017.11:g.31182578G>A
NG_009018.1:g.92602G>A
NM_000267.3:c.801G>A
NM_001042492.3:c.801G>AMANE SELECT
NM_001128147.3:c.801G>A
NP_000258.1:p.Trp267Ter
NP_001035957.1:p.Trp267Ter
NP_001121619.1:p.Trp267Ter
LRG_214t1:c.801G>A
LRG_214:g.92602G>A
LRG_214p1:p.Trp267Ter
NC_000017.10:g.29509596G>A
NM_001042492.2:c.801G>A
NM_001042492.3:c.801G>A

Protein change:

W267*

Links:

dbSNP: rs1064794273

NCBI 1000 Genomes Browser:

rs1064794273

Molecular consequence:

NM_000267.3:c.801G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001042492.3:c.801G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001128147.3:c.801G>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000828415	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 24, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 8834249, 14635100, 10712197, 23913538, 28492532
SCV001479205	Genome Diagnostics Laboratory, The Hospital for Sick Children	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 26, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002561603	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 15, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004176908	Clinical Genomics Laboratory, Washington University in St. Louis	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 25, 2023)	somatic	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005086754	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 17, 2023)	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	somatic	yes	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
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Scanning the first part of the neurofibromatosis type 1 gene by RNA-SSCP: identification of three novel mutations and of two new polymorphisms.

Gasparini P, D'Agruma L, Pio de Cillis G, Balestrazzi P, Mingarelli R, Zelante L.

Hum Genet. 1996 Apr;97(4):492-5.

PubMed [citation]

PMID:: 8834249

Somatic NF1 mutation spectra in a family with neurofibromatosis type 1: toward a theory of genetic modifiers.

Wiest V, Eisenbarth I, Schmegner C, Krone W, Assum G.

Hum Mutat. 2003 Dec;22(6):423-7.

PubMed [citation]

PMID:: 14635100

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000828415.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

ClinVar contains an entry for this variant (Variation ID: 420075). This premature translational stop signal has been observed in individuals with neurofibromatosis type 1 (PMID: 8834249, 10712197, 14635100). 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 creates a premature translational stop signal (p.Trp267*) in the NF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). 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 Genome Diagnostics Laboratory, The Hospital for Sick Children, SCV001479205.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002561603.1

#	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

From Clinical Genomics Laboratory, Washington University in St. Louis, SCV004176908.1

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

Description

An NF1 c.801G>A (p.Trp267Ter) variant was identified at an allelic fraction consistent with somatic origin. This variant has been previously reported in at least five individuals affected with neurofibromatosis type 1 (Gasparini P et al., PMID: 8834249; Fahsold R et al., PMID: 10712197; Wiest V et al., PMID: 14635100). The NF1 c.801G>A (p.Trp267Ter) variant has been reported in the ClinVar database as a pathogenic variant by multiple submitters (ClinVar Variation ID: 420075), and it has been reported in four cases in the cancer database COSMIC. This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. The NF1 c.801G>A (p.Trp267Ter) variant introduces a premature termination codon, resulting in a transcript that is predicted to undergo nonsense-mediated decay. Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the NF1 c.801G>A (p.Trp267Ter) variant is classified as pathogenic.Of note, this assay cannot determine if the two pathogenic NF1 variants identified in this patient are in cis or in trans.

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086754.1

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated juvenile myelomonocytic leukemia (MIM#607785), familial spinal neurofibromatosis (MIM#162210), neurofibromatosis type 1 (MIM#162200), neurofibromatosis-Noonan syndrome (MIM#601321) and Watson syndrome (MIM#193520). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Disease manifestation can be extremely variable, even within a family (GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been classified as likely pathogenic or pathogenic (DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories and has been reported in multiple unrelated individuals with neurofibromatosis type 1 (ClinVar). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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: Jan 19, 2025

ClinVar

Relating variation to medicine