NM_000268.4(NF2):c.185T>C (p.Phe62Ser) AND Neurofibromatosis, type 2

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 17, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000003458.5

Allele description [Variation Report for NM_000268.4(NF2):c.185T>C (p.Phe62Ser)]

NM_000268.4(NF2):c.185T>C (p.Phe62Ser)

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.185T>C (p.Phe62Ser)

HGVS:

NC_000022.11:g.29636821T>C
NG_009057.1:g.38266T>C
NM_000268.4:c.185T>CMANE SELECT
NM_016418.5:c.185T>C
NM_181825.3:c.185T>C
NM_181828.3:c.115-2269T>C
NM_181829.3:c.185T>C
NM_181830.3:c.115-5381T>C
NM_181831.3:c.115-5381T>C
NM_181832.3:c.185T>C
NM_181833.3:c.185T>C
NP_000259.1:p.Phe62Ser
NP_057502.2:p.Phe62Ser
NP_861546.1:p.Phe62Ser
NP_861967.1:p.Phe62Ser
NP_861970.1:p.Phe62Ser
NP_861971.1:p.Phe62Ser
LRG_511t2:c.185T>C
LRG_511:g.38266T>C
LRG_511p2:p.Phe62Ser
NC_000022.10:g.30032810T>C
NR_156186.2:n.667T>C
P35240:p.Phe62Ser

Protein change:

F62S; PHE62SER

Links:

UniProtKB: P35240#VAR_000810; OMIM: 607379.0016; dbSNP: rs121434261

NCBI 1000 Genomes Browser:

rs121434261

Molecular consequence:

NM_181828.3:c.115-2269T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_181830.3:c.115-5381T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_181831.3:c.115-5381T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000268.4:c.185T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_016418.5:c.185T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_181825.3:c.185T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_181829.3:c.185T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_181832.3:c.185T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_181833.3:c.185T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_156186.2:n.667T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000023616	OMIM	no assertion criteria provided	Pathogenic (Aug 1, 2002)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 8757035, 8081368, 12118253
SCV004298849	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 17, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 8081368, 8757035, 12118253, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000023616

OMIM

no assertion criteria provided

Pathogenic
(Aug 1, 2002)

germline

literature only

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

SCV004298849

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 17, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Germline mutations in the neurofibromatosis type 2 tumour suppressor gene.

Bourn D, Carter SA, Mason S, Gareth D, Evans R, Strachan T.

Hum Mol Genet. 1994 May;3(5):813-6.

PubMed [citation]

PMID:: 8081368

A missense mutation in the neurofibromatosis 2 gene occurs in patients with mild and severe phenotypes.

Scoles DR, Baser ME, Pulst SM.

Neurology. 1996 Aug;47(2):544-6.

PubMed [citation]

PMID:: 8757035

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000023616.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

Description

Scoles et al. (1996) found a T-to-C transition at nucleotide 185 in exon 2 of the NFw gene, resulting in a substitution of serine for phenylalanine-62, in a family with both mild and severe neurofibromatosis type II (SWNV; 101000) phenotypes. This mutation had previously been reported by Bourn et al. (1994) in a family in which the phenotype of neurofibromatosis type II was uniformly mild.

Paxillin (602505) is an adaptor protein that integrates adhesion- and growth factor-dependent signals with changes in actin organization and gene expression. Paxillin contains several protein-protein binding motifs. Fernandez-Valle et al. (2002) showed that the molecular adaptor paxillin binds directly to schwannomin at residues 50-70, which are encoded by exon 2. This interaction mediates the membrane localization of schwannomin to the plasma membrane, where it associates with beta-1-integrin (135630) and ERBB2 (164870). The work defined a pathogenic mechanism for the development of NF2 in humans with mutations in exon 2 of NF2.

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

From Invitae, SCV004298849.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 62 of the NF2 protein (p.Phe62Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of NF2-related conditions (PMID: 8081368, 8757035; Invitae). ClinVar contains an entry for this variant (Variation ID: 3297). 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 NF2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NF2 function (PMID: 12118253). 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.

#	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

Last Updated: Feb 20, 2024

ClinVar

Relating variation to medicine