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NM_001042492.3(NF1):c.5651T>G (p.Phe1884Cys) AND Neurofibromatosis, type 1

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Jan 16, 2024
Review status:
criteria provided, conflicting classifications
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:
RCV002470271.3

Allele description [Variation Report for NM_001042492.3(NF1):c.5651T>G (p.Phe1884Cys)]

NM_001042492.3(NF1):c.5651T>G (p.Phe1884Cys)

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.5651T>G (p.Phe1884Cys)
HGVS:
  • NC_000017.11:g.31330337T>G
  • NG_009018.1:g.240361T>G
  • NM_000267.3:c.5588T>G
  • NM_001042492.3:c.5651T>GMANE SELECT
  • NP_000258.1:p.Phe1863Cys
  • NP_001035957.1:p.Phe1884Cys
  • NP_001035957.1:p.Phe1884Cys
  • LRG_214t1:c.5588T>G
  • LRG_214t2:c.5651T>G
  • LRG_214:g.240361T>G
  • LRG_214p1:p.Phe1863Cys
  • LRG_214p2:p.Phe1884Cys
  • NC_000017.10:g.29657355T>G
  • NM_001042492.2:c.5651T>G
Protein change:
F1863C
Molecular consequence:
  • NM_000267.3:c.5588T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042492.3:c.5651T>G - 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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV002767003Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Sep 2, 2022)
germlineclinical testing

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

SCV004296780Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Jan 16, 2024)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Phenotypic expression of a spectrum of Neurofibromatosis Type 1 (NF1) mutations identified through NGS and MLPA.

Tsipi M, Poulou M, Fylaktou I, Kosma K, Tsoutsou E, Pons MR, Kokkinou E, Kitsiou-Tzeli S, Fryssira H, Tzetis M.

J Neurol Sci. 2018 Dec 15;395:95-105. doi: 10.1016/j.jns.2018.10.006. Epub 2018 Oct 4.

PubMed [citation]
PMID:
30308447

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753
See all PubMed Citations (6)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767003.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurofibromatosis, type 1 (MIM#162200). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated SEC14 domain and pleckstrin homology domain (PMID: 30290804). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. This alternative change (p.(Phe1884Leu)) has been reported once as a VUS (LOVD). It has also been reported as likely pathogenic and pathogenic, and observed in several individuals with neurofibromatosis (NF) (ClinVar, PMID: 27838393, PMID: 30308447). Another comparable variant (p.(Phe1884Val)) has been reported as a VUS (ClinVar, LOVD). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been observed in a single individual with NF (PMID: 30290804) and reported as pathogenic (LOVD). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004296780.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 1863 of the NF1 protein (p.Phe1863Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 30290804). ClinVar contains an entry for this variant (Variation ID: 1805987). 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 with a positive predictive value of 95%. This variant disrupts the p.Phe1863 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22190595, 27838393; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

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

Last Updated: Sep 29, 2024