NM_000268.4(NF2):c.1340G>T (p.Arg447Met) AND Neurofibromatosis, type 2

Clinical significance:Uncertain significance (Last evaluated: May 24, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001054899.1

Allele description [Variation Report for NM_000268.4(NF2):c.1340G>T (p.Arg447Met)]

NM_000268.4(NF2):c.1340G>T (p.Arg447Met)

Gene:
NF2:NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
22q12.2
Genomic location:
Preferred name:
NM_000268.4(NF2):c.1340G>T (p.Arg447Met)
HGVS:
  • NC_000022.11:g.29673486G>T
  • NG_009057.1:g.74931G>T
  • NM_000268.4:c.1340G>TMANE SELECT
  • NM_016418.5:c.1340G>T
  • NM_181825.3:c.1340G>T
  • NM_181828.3:c.1214G>T
  • NM_181829.3:c.1217G>T
  • NM_181830.3:c.1091G>T
  • NM_181831.3:c.1091G>T
  • NM_181832.3:c.1340G>T
  • NM_181833.3:c.448-21266G>T
  • NP_000259.1:p.Arg447Met
  • NP_057502.2:p.Arg447Met
  • NP_861546.1:p.Arg447Met
  • NP_861966.1:p.Arg405Met
  • NP_861967.1:p.Arg406Met
  • NP_861968.1:p.Arg364Met
  • NP_861969.1:p.Arg364Met
  • NP_861970.1:p.Arg447Met
  • LRG_511t1:c.1340G>T
  • LRG_511t2:c.1340G>T
  • LRG_511:g.74931G>T
  • LRG_511p2:p.Arg447Met
  • NC_000022.10:g.30069475G>T
  • NM_000268.3:c.1340G>T
  • NR_156186.2:n.1822G>T
Protein change:
R364M
Links:
dbSNP: rs2066868182
NCBI 1000 Genomes Browser:
rs2066868182
Molecular consequence:
  • NM_181833.3:c.448-21266G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000268.4:c.1340G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_016418.5:c.1340G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181825.3:c.1340G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181828.3:c.1214G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181829.3:c.1217G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181830.3:c.1091G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181831.3:c.1091G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181832.3:c.1340G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_156186.2:n.1822G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Neurofibromatosis, type 2 (NF2)
Synonyms:
NF 2; Neurofibromatosis central type; Acoustic schwannomas bilateral; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007039; MedGen: C0027832; Orphanet: 637; OMIM: 101000

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001219257Invitaecriteria provided, single submitter
Uncertain significance
(May 24, 2019)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV001219257.1

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

Description

This sequence change replaces arginine with methionine at codon 447 of the NF2 protein (p.Arg447Met). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and methionine. This variant also falls at the last nucleotide of exon 12 of the NF2 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with clinical features of neurofibromatosis type 2 (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. 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: Nov 27, 2021

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