NM_000268.4(NF2):c.1232G>A (p.Arg411His) AND Neurofibromatosis, type 2

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 29, 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:: RCV000632640.10

Allele description [Variation Report for NM_000268.4(NF2):c.1232G>A (p.Arg411His)]

NM_000268.4(NF2):c.1232G>A (p.Arg411His)

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.1232G>A (p.Arg411His)

HGVS:

NC_000022.11:g.29673378G>A
NG_009057.1:g.74823G>A
NM_000268.4:c.1232G>AMANE SELECT
NM_016418.5:c.1232G>A
NM_181825.3:c.1232G>A
NM_181828.3:c.1106G>A
NM_181829.3:c.1109G>A
NM_181830.3:c.983G>A
NM_181831.3:c.983G>A
NM_181832.3:c.1232G>A
NM_181833.3:c.448-21374G>A
NP_000259.1:p.Arg411His
NP_000259.1:p.Arg411His
NP_057502.2:p.Arg411His
NP_861546.1:p.Arg411His
NP_861966.1:p.Arg369His
NP_861967.1:p.Arg370His
NP_861968.1:p.Arg328His
NP_861969.1:p.Arg328His
NP_861970.1:p.Arg411His
LRG_511t1:c.1232G>A
LRG_511t2:c.1232G>A
LRG_511:g.74823G>A
LRG_511p1:p.Arg411His
LRG_511p2:p.Arg411His
NC_000022.10:g.30069367G>A
NM_000268.3(NF2):c.1232G>A
NM_000268.3:c.1232G>A
NR_156186.2:n.1714G>A
p.Arg411His

Protein change:

R328H

Links:

dbSNP: rs201214090

NCBI 1000 Genomes Browser:

rs201214090

Molecular consequence:

NM_181833.3:c.448-21374G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000268.4:c.1232G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_016418.5:c.1232G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181825.3:c.1232G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181828.3:c.1106G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181829.3:c.1109G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181830.3:c.983G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181831.3:c.983G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_181832.3:c.1232G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_156186.2:n.1714G>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
SCV000753825	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 29, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002044881	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]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000753825

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 29, 2024)

germline

clinical testing

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

SCV002044881

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]

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
not provided	germline	no	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

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, SCV000753825.7

#	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 arginine, which is basic and polar, with histidine, which is basic and polar, at codon 411 of the NF2 protein (p.Arg411His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with NF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 527695). 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 with a negative predictive value of 80%. 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

From Genome-Nilou Lab, SCV002044881.1

#	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

Last Updated: Oct 8, 2024

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