NM_000268.4(NF2):c.1400G>A (p.Arg467Lys) AND Neurofibromatosis, type 2

Clinical significance:Uncertain significance (Last evaluated: Nov 6, 2018)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000810207.2

Allele description [Variation Report for NM_000268.4(NF2):c.1400G>A (p.Arg467Lys)]

NM_000268.4(NF2):c.1400G>A (p.Arg467Lys)

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.1400G>A (p.Arg467Lys)
HGVS:
  • NC_000022.11:g.29674895G>A
  • NG_009057.1:g.76340G>A
  • NM_000268.3:c.1400G>A
  • NM_000268.4:c.1400G>AMANE SELECT
  • NM_016418.5:c.1400G>A
  • NM_181825.3:c.1400G>A
  • NM_181828.3:c.1274G>A
  • NM_181829.3:c.1277G>A
  • NM_181830.3:c.1151G>A
  • NM_181831.3:c.1151G>A
  • NM_181832.3:c.1400G>A
  • NM_181833.3:c.448-19857G>A
  • NP_000259.1:p.Arg467Lys
  • NP_000259.1:p.Arg467Lys
  • NP_057502.2:p.Arg467Lys
  • NP_861546.1:p.Arg467Lys
  • NP_861966.1:p.Arg425Lys
  • NP_861967.1:p.Arg426Lys
  • NP_861968.1:p.Arg384Lys
  • NP_861969.1:p.Arg384Lys
  • NP_861970.1:p.Arg467Lys
  • LRG_511t1:c.1400G>A
  • LRG_511t2:c.1400G>A
  • LRG_511:g.76340G>A
  • LRG_511p1:p.Arg467Lys
  • LRG_511p2:p.Arg467Lys
  • NC_000022.10:g.30070884G>A
  • NR_156186.2:n.1882G>A
Protein change:
R384K
Links:
dbSNP: rs1294032875
NCBI 1000 Genomes Browser:
rs1294032875
Molecular consequence:
  • NM_181833.3:c.448-19857G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000268.3:c.1400G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000268.4:c.1400G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_016418.5:c.1400G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181825.3:c.1400G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181828.3:c.1274G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181829.3:c.1277G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181830.3:c.1151G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181831.3:c.1151G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_181832.3:c.1400G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_156186.2:n.1882G>A - 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
SCV000950400Invitaecriteria provided, single submitter
Uncertain significance
(Nov 6, 2018)
germlineclinical testing

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

SCV001306001Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Uncertain significance
(Apr 27, 2017)
germlineclinical testing

Citation Link

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, SCV000950400.1

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

Description

This sequence change replaces arginine with lysine at codon 467 of the NF2 protein (p.Arg467Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. 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 disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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

From Illumina Clinical Services Laboratory,Illumina, SCV001306001.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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

Last Updated: Oct 24, 2021

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