NM_000268.4(NF2):c.1351G>A (p.Ala451Thr) AND Neurofibromatosis, type 2

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 9, 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:: RCV003607711.2

Allele description [Variation Report for NM_000268.4(NF2):c.1351G>A (p.Ala451Thr)]

NM_000268.4(NF2):c.1351G>A (p.Ala451Thr)

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.1351G>A (p.Ala451Thr)

HGVS:

NC_000022.11:g.29674846G>A
NG_009057.1:g.76291G>A
NM_000268.4:c.1351G>AMANE SELECT
NM_001407053.1:c.1237G>A
NM_001407054.1:c.1228G>A
NM_001407055.1:c.1225G>A
NM_001407056.1:c.1237G>A
NM_001407057.1:c.1216G>A
NM_001407058.1:c.1228G>A
NM_001407059.1:c.1216G>A
NM_001407060.1:c.1351G>A
NM_001407062.1:c.1093G>A
NM_001407063.1:c.1102G>A
NM_001407064.1:c.1102G>A
NM_001407065.1:c.817G>A
NM_001407066.1:c.1351G>A
NM_001407067.1:c.1120G>A
NM_016418.5:c.1351G>A
NM_181825.3:c.1351G>A
NM_181828.3:c.1225G>A
NM_181829.3:c.1228G>A
NM_181830.3:c.1102G>A
NM_181831.3:c.1102G>A
NM_181832.3:c.1351G>A
NM_181833.3:c.448-19906G>A
NP_000259.1:p.Ala451Thr
NP_000259.1:p.Ala451Thr
NP_001393982.1:p.Ala413Thr
NP_001393983.1:p.Ala410Thr
NP_001393984.1:p.Ala409Thr
NP_001393985.1:p.Ala413Thr
NP_001393986.1:p.Ala406Thr
NP_001393987.1:p.Ala410Thr
NP_001393988.1:p.Ala406Thr
NP_001393989.1:p.Ala451Thr
NP_001393991.1:p.Ala365Thr
NP_001393992.1:p.Ala368Thr
NP_001393993.1:p.Ala368Thr
NP_001393994.1:p.Ala273Thr
NP_001393995.1:p.Ala451Thr
NP_001393996.1:p.Ala374Thr
NP_057502.2:p.Ala451Thr
NP_861546.1:p.Ala451Thr
NP_861966.1:p.Ala409Thr
NP_861967.1:p.Ala410Thr
NP_861968.1:p.Ala368Thr
NP_861969.1:p.Ala368Thr
NP_861970.1:p.Ala451Thr
LRG_511t1:c.1351G>A
LRG_511t2:c.1351G>A
LRG_511:g.76291G>A
LRG_511p1:p.Ala451Thr
LRG_511p2:p.Ala451Thr
NC_000022.10:g.30070835G>A
NM_000268.3:c.1351G>A
NR_156186.2:n.1833G>A
NR_176267.1:n.899G>A

Protein change:

A273T

Molecular consequence:

NM_181833.3:c.448-19906G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000268.4:c.1351G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407053.1:c.1237G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407054.1:c.1228G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407055.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407056.1:c.1237G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407057.1:c.1216G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407058.1:c.1228G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407059.1:c.1216G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407060.1:c.1351G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407062.1:c.1093G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407063.1:c.1102G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407064.1:c.1102G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407065.1:c.817G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407066.1:c.1351G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407067.1:c.1120G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_016418.5:c.1351G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181825.3:c.1351G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181828.3:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181829.3:c.1228G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181830.3:c.1102G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181831.3:c.1102G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181832.3:c.1351G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_176267.1:n.899G>A - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004390318	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 9, 2023)	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

SCV004390318

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 9, 2023)

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	not provided	not provided	not provided	not provided	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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004390318.1

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

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 451 of the NF2 protein (p.Ala451Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF2-related conditions. 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 not expected to disrupt NF2 protein function. 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: Sep 29, 2024

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