NM_001042492.3(NF1):c.1260+5G>C AND Neurofibromatosis, type 1

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 14, 2022
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:: RCV000462352.8

Allele description [Variation Report for NM_001042492.3(NF1):c.1260+5G>C]

NM_001042492.3(NF1):c.1260+5G>C

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.1260+5G>C

HGVS:

NC_000017.11:g.31201490G>C
NG_009018.1:g.111514G>C
NM_000267.3:c.1260+5G>C
NM_001042492.3:c.1260+5G>CMANE SELECT
NM_001128147.3:c.1260+5G>C
LRG_214t1:c.1260+5G>C
LRG_214:g.111514G>C
NC_000017.10:g.29528508G>C

Links:

dbSNP: rs1060500253

NCBI 1000 Genomes Browser:

rs1060500253

Molecular consequence:

NM_000267.3:c.1260+5G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001042492.3:c.1260+5G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001128147.3:c.1260+5G>C - intron variant - [Sequence Ontology: SO:0001627]

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
SCV000541982	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 14, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 25074460, 29483232, 17576681, 9536098, 12807981, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000541982

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 14, 2022)

germline

clinical testing

PubMed (6)
[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

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

Whole Exome Sequencing Reveals a Monogenic Cause of Disease in ≈43% of 35 Families With Midaortic Syndrome.

Warejko JK, Schueler M, Vivante A, Tan W, Daga A, Lawson JA, Braun DA, Shril S, Amann K, Somers MJG, Rodig NM, Baum MA, Daouk G, Traum AZ, Kim HB, Vakili K, Porras D, Lock J, Rivkin MJ, Chaudry G, Smoot LB, Singh MN, et al.

Hypertension. 2018 Apr;71(4):691-699. doi: 10.1161/HYPERTENSIONAHA.117.10296. Epub 2018 Feb 26.

PubMed [citation]

PMID:: 29483232
PMCID:: PMC5843550

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000541982.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the c.1260+5G nucleotide in the NF1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 25074460, 29483232; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 404430). This variant has been observed in individual(s) with clinical features of neurofibromatosis type 1 and/or neurofibromatosis type 1 (PMID: 12807981; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 11 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein. It affects a nucleotide within the consensus splice site.

#	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

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