NM_000268.4(NF2):c.1635A>T (p.Glu545Asp) AND Neurofibromatosis, type 2

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jul 28, 2023
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:: RCV000703302.15

Allele description [Variation Report for NM_000268.4(NF2):c.1635A>T (p.Glu545Asp)]

NM_000268.4(NF2):c.1635A>T (p.Glu545Asp)

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.1635A>T (p.Glu545Asp)

HGVS:

NC_000022.11:g.29681499A>T
NG_009057.1:g.82944A>T
NM_000268.4:c.1635A>TMANE SELECT
NM_016418.5:c.1635A>T
NM_181825.3:c.1635A>T
NM_181828.3:c.1509A>T
NM_181829.3:c.1512A>T
NM_181830.3:c.1386A>T
NM_181831.3:c.1386A>T
NM_181832.3:c.1635A>T
NM_181833.3:c.448-13253A>T
NP_000259.1:p.Glu545Asp
NP_000259.1:p.Glu545Asp
NP_057502.2:p.Glu545Asp
NP_861546.1:p.Glu545Asp
NP_861966.1:p.Glu503Asp
NP_861967.1:p.Glu504Asp
NP_861968.1:p.Glu462Asp
NP_861969.1:p.Glu462Asp
NP_861970.1:p.Glu545Asp
LRG_511t1:c.1635A>T
LRG_511t2:c.1635A>T
LRG_511:g.82944A>T
LRG_511p1:p.Glu545Asp
LRG_511p2:p.Glu545Asp
NC_000022.10:g.30077488A>T
NM_000268.3:c.1635A>T
NR_156186.2:n.2117A>T

Protein change:

E462D

Links:

dbSNP: rs1556003698

NCBI 1000 Genomes Browser:

rs1556003698

Molecular consequence:

NM_181833.3:c.448-13253A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000268.4:c.1635A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_016418.5:c.1635A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_181825.3:c.1635A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_181828.3:c.1509A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_181829.3:c.1512A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_181830.3:c.1386A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_181831.3:c.1386A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_181832.3:c.1635A>T - missense variant - [Sequence Ontology: SO:0001583]
NR_156186.2:n.2117A>T - 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

Recent activity

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DA499080 FCBBF3 Homo sapiens cDNA clone FCBBF3012656 5', mRNA sequence
DA499080 FCBBF3 Homo sapiens cDNA clone FCBBF3012656 5', mRNA sequence
gi|80788158|gnl|dbEST|33244395|dbj| 080.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000832198	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 28, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002044905	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004832114	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jun 8, 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

SCV000832198

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 28, 2023)

germline

clinical testing

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

SCV002044905

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 7, 2021)

germline

clinical testing

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

SCV004832114

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jun 8, 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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
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, SCV000832198.7

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

Description

This variant has not been reported in the literature in individuals affected 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. 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. ClinVar contains an entry for this variant (Variation ID: 435976). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 545 of the NF2 protein (p.Glu545Asp).

#	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 Genome-Nilou Lab, SCV002044905.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004832114.1

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

Description

This missense variant replaces glutamic acid with aspartic acid at codon 545 of the NF2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with NF2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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