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NM_001042492.3(NF1):c.1884del (p.Phe627_Tyr628insTer) AND Neurofibromatosis, type 1

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Feb 24, 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:
RCV001045101.5

Allele description [Variation Report for NM_001042492.3(NF1):c.1884del (p.Phe627_Tyr628insTer)]

NM_001042492.3(NF1):c.1884del (p.Phe627_Tyr628insTer)

Gene:
NF1:neurofibromin 1 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
17q11.2
Genomic location:
Preferred name:
NM_001042492.3(NF1):c.1884del (p.Phe627_Tyr628insTer)
HGVS:
  • NC_000017.11:g.31225133del
  • NG_009018.1:g.135157del
  • NM_000267.3:c.1884del
  • NM_001042492.3:c.1884delMANE SELECT
  • NP_000258.1:p.Phe627_Tyr628insTer
  • NP_001035957.1:p.Phe627_Tyr628insTer
  • LRG_214t1:c.1884del
  • LRG_214:g.135157del
  • LRG_214p1:p.Phe627_Tyr628insTer
  • NC_000017.10:g.29552151del
  • NM_000267.3:c.1884delC
Links:
dbSNP: rs2066990429
NCBI 1000 Genomes Browser:
rs2066990429
Molecular consequence:
  • NM_000267.3:c.1884del - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001042492.3:c.1884del - nonsense - [Sequence Ontology: SO:0001587]

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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001208934Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 25, 2019) 		germlineclinical testing

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

SCV003845158Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Likely pathogenic
(Feb 24, 2023) 		germlineclinical testing

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience.

Sabbagh A, Pasmant E, Imbard A, Luscan A, Soares M, Blanché H, Laurendeau I, Ferkal S, Vidaud M, Pinson S, Bellanné-Chantelot C, Vidaud D, Parfait B, Wolkenstein P.

Hum Mutat. 2013 Nov;34(11):1510-8. doi: 10.1002/humu.22392. Epub 2013 Aug 26.

PubMed [citation]
PMID:
23913538
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001208934.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). A different variant (c.1884C>A) giving rise to the same protein effect observed here (p.Tyr628*) has been determined to be pathogenic (Invitae). This suggests that this variant is also likely to be causative of disease. This variant has not been reported in the literature in individuals with NF1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr628*) in the NF1 gene. It is expected to result in an absent or disrupted protein product.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003845158.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Variant summary: NF1 c.1884delC (p.Tyr628X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251210 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1884delC in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites this variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 20, 2024