NM_000268.4(NF2):c.999G>C (p.Gln333His) AND Neurofibromatosis, type 2

Clinical significance:Uncertain significance (Last evaluated: Mar 4, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_000268.4(NF2):c.999G>C (p.Gln333His)]

NM_000268.4(NF2):c.999G>C (p.Gln333His)

NF2:NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000268.4(NF2):c.999G>C (p.Gln333His)
  • NC_000022.11:g.29668446G>C
  • NG_009057.1:g.69891G>C
  • NM_000268.4:c.999G>CMANE SELECT
  • NM_016418.5:c.999G>C
  • NM_181825.3:c.999G>C
  • NM_181828.3:c.873G>C
  • NM_181829.3:c.876G>C
  • NM_181830.3:c.750G>C
  • NM_181831.3:c.750G>C
  • NM_181832.3:c.999G>C
  • NM_181833.3:c.447+26161G>C
  • NP_000259.1:p.Gln333His
  • NP_057502.2:p.Gln333His
  • NP_861546.1:p.Gln333His
  • NP_861966.1:p.Gln291His
  • NP_861967.1:p.Gln292His
  • NP_861968.1:p.Gln250His
  • NP_861969.1:p.Gln250His
  • NP_861970.1:p.Gln333His
  • LRG_511t1:c.999G>C
  • LRG_511t2:c.999G>C
  • LRG_511:g.69891G>C
  • LRG_511p2:p.Gln333His
  • NC_000022.10:g.30064435G>C
  • NM_000268.3:c.999G>C
  • NR_156186.2:n.1481G>C
Protein change:
dbSNP: rs1469191017
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_181833.3:c.447+26161G>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000268.4:c.999G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_016418.5:c.999G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181825.3:c.999G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181828.3:c.873G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181829.3:c.876G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181830.3:c.750G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181831.3:c.750G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181832.3:c.999G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_156186.2:n.1481G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]


Neurofibromatosis, type 2 (NF2)
NF 2; Neurofibromatosis central type; Acoustic schwannomas bilateral; See all synonyms [MedGen]
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)
SCV001212671Invitaecriteria provided, single submitter
Uncertain significance
(Mar 4, 2019)
germlineclinical testing

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

Summary from all submissions

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



Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001212671.2

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


This sequence change replaces glutamine with histidine at codon 333 of the NF2 protein (p.Gln333His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant also falls at the last nucleotide of exon 10 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 not been reported in the literature in individuals with NF2-related conditions. 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: Deleterious; PolyPhen-2: Possibly 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.

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

Last Updated: Nov 27, 2021

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