NM_000268.4(NF2):c.263A>G (p.Lys88Arg) AND Neurofibromatosis, type 2

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 11, 2024
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:: RCV001214722.9

Allele description [Variation Report for NM_000268.4(NF2):c.263A>G (p.Lys88Arg)]

NM_000268.4(NF2):c.263A>G (p.Lys88Arg)

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.263A>G (p.Lys88Arg)

HGVS:

NC_000022.11:g.29639112A>G
NG_009057.1:g.40557A>G
NM_000268.4:c.263A>GMANE SELECT
NM_016418.5:c.263A>G
NM_181825.3:c.263A>G
NM_181828.3:c.137A>G
NM_181829.3:c.240+2236A>G
NM_181830.3:c.115-3090A>G
NM_181831.3:c.115-3090A>G
NM_181832.3:c.263A>G
NM_181833.3:c.263A>G
NP_000259.1:p.Lys88Arg
NP_057502.2:p.Lys88Arg
NP_861546.1:p.Lys88Arg
NP_861966.1:p.Lys46Arg
NP_861970.1:p.Lys88Arg
NP_861971.1:p.Lys88Arg
LRG_511t1:c.263A>G
LRG_511t2:c.263A>G
LRG_511:g.40557A>G
LRG_511p2:p.Lys88Arg
NC_000022.10:g.30035101A>G
NM_000268.3:c.263A>G
NR_156186.2:n.745A>G

Protein change:

K46R

Links:

dbSNP: rs547255779

NCBI 1000 Genomes Browser:

rs547255779

Molecular consequence:

NM_181829.3:c.240+2236A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_181830.3:c.115-3090A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_181831.3:c.115-3090A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000268.4:c.263A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_016418.5:c.263A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_181825.3:c.263A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_181828.3:c.137A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_181832.3:c.263A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_181833.3:c.263A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_156186.2:n.745A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Neurofibromatosis, type 2 (SWNV)
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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001386421	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 11, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004838902	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 11, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001386421

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 11, 2019)

germline

clinical testing

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

SCV004838902

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jan 11, 2024)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical 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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001386421.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant is present in population databases (rs547255779, ExAC 0.01%). This sequence change replaces lysine with arginine at codon 88 of the NF2 protein (p.Lys88Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant has not been reported in the literature in individuals with NF2-related conditions. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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").

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004838902.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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