NM_001042492.3(NF1):c.4578-2A>G AND Neurofibromatosis, type 1

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 12, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000541202.4

Allele description [Variation Report for NM_001042492.3(NF1):c.4578-2A>G]

NM_001042492.3(NF1):c.4578-2A>G

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.4578-2A>G

HGVS:

NC_000017.11:g.31261709A>G
NG_009018.1:g.171733A>G
NM_000267.3:c.4515-2A>G
NM_001042492.3:c.4578-2A>GMANE SELECT
LRG_214t1:c.4515-2A>G
LRG_214:g.171733A>G
NC_000017.10:g.29588727A>G

Links:

dbSNP: rs1555618996

NCBI 1000 Genomes Browser:

rs1555618996

Molecular consequence:

NM_000267.3:c.4515-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001042492.3:c.4578-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

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

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
SCV000628602	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 12, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10712197, 10862084, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000628602

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 12, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Citations

PubMed

Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain.

Fahsold R, Hoffmeyer S, Mischung C, Gille C, Ehlers C, Kücükceylan N, Abdel-Nour M, Gewies A, Peters H, Kaufmann D, Buske A, Tinschert S, Nürnberg P.

Am J Hum Genet. 2000 Mar;66(3):790-818.

PubMed [citation]

PMID:: 10712197
PMCID:: PMC1288164

Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects.

Messiaen LM, Callens T, Mortier G, Beysen D, Vandenbroucke I, Van Roy N, Speleman F, Paepe AD.

Hum Mutat. 2000;15(6):541-55.

PubMed [citation]

PMID:: 10862084

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000628602.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in activation of cryptic splice sites and introduces a premature termination codon (PMID: 10862084; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 457705). Disruption of this splice site has been observed in individual(s) with neurofibromatosis type I (PMID: 10712197, 10862084). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 33 of the NF1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.

#	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

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine