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NM_001042492.3(NF1):c.5476C>G (p.His1826Asp) AND Neurofibromatosis, type 1

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Aug 17, 2022
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:
RCV000497149.6

Allele description [Variation Report for NM_001042492.3(NF1):c.5476C>G (p.His1826Asp)]

NM_001042492.3(NF1):c.5476C>G (p.His1826Asp)

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.5476C>G (p.His1826Asp)
HGVS:
  • NC_000017.11:g.31327706C>G
  • NG_009018.1:g.237730C>G
  • NM_000267.3:c.5413C>G
  • NM_001042492.3:c.5476C>GMANE SELECT
  • NP_000258.1:p.His1805Asp
  • NP_001035957.1:p.His1826Asp
  • NP_001035957.1:p.His1826Asp
  • LRG_214t1:c.5413C>G
  • LRG_214t2:c.5476C>G
  • LRG_214:g.237730C>G
  • LRG_214p1:p.His1805Asp
  • LRG_214p2:p.His1826Asp
  • NC_000017.10:g.29654724C>G
  • NM_001042492.2:c.5476C>G
Protein change:
H1805D
Links:
dbSNP: rs1135402871
NCBI 1000 Genomes Browser:
rs1135402871
Molecular consequence:
  • NM_000267.3:c.5413C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042492.3:c.5476C>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
SCV000588799Medical Genetics, University of Parma
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Aug 17, 2022)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001541863Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Aug 27, 2021)
germlineclinical testing

PubMed (2)
[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

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

Patterns of Novel Alleles and Genotype/Phenotype Correlations Resulting from the Analysis of 108 Previously Undetected Mutations in Patients Affected by Neurofibromatosis Type I.

Bonatti F, Adorni A, Matichecchia A, Mozzoni P, Uliana V, Pisani F, Garavelli L, Graziano C, Gnoli M, Carli D, Bigoni S, Boschi E, Martorana D, Percesepe A.

Int J Mol Sci. 2017 Sep 29;18(10). doi:pii: E2071. 10.3390/ijms18102071.

PubMed [citation]
PMID:
28961165
PMCID:
PMC5666753
See all PubMed Citations (3)

Details of each submission

From Medical Genetics, University of Parma, SCV000588799.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001541863.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

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. 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. This variant has been observed in individual(s) with neurofibromatosis type 1 (PMID: 28961165). ClinVar contains an entry for this variant (Variation ID: 431655). This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with aspartic acid at codon 1805 of the NF1 protein (p.His1805Asp). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and aspartic acid.

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

Last Updated: Oct 8, 2024