NM_000268.4(NF2):c.517-1G>A AND Neurofibromatosis, type 2

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jul 8, 2022
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:: RCV001202383.11

Allele description [Variation Report for NM_000268.4(NF2):c.517-1G>A]

NM_000268.4(NF2):c.517-1G>A

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.517-1G>A

HGVS:

NC_000022.11:g.29655593G>A
NG_009057.1:g.57038G>A
NM_000268.4:c.517-1G>AMANE SELECT
NM_001407053.1:c.403-1G>A
NM_001407054.1:c.394-1G>A
NM_001407055.1:c.391-1G>A
NM_001407056.1:c.403-1G>A
NM_001407057.1:c.517-1G>A
NM_001407058.1:c.394-1G>A
NM_001407059.1:c.517-1G>A
NM_001407060.1:c.517-1G>A
NM_001407062.1:c.394-1G>A
NM_001407063.1:c.268-1G>A
NM_001407064.1:c.268-1G>A
NM_001407065.1:c.-18-1G>A
NM_001407066.1:c.517-1G>A
NM_001407067.1:c.286-1G>A
NM_016418.5:c.517-1G>A
NM_181825.3:c.517-1G>A
NM_181828.3:c.391-1G>A
NM_181829.3:c.394-1G>A
NM_181830.3:c.268-1G>A
NM_181831.3:c.268-1G>A
NM_181832.3:c.517-1G>A
NM_181833.3:c.447+13308G>A
LRG_511t1:c.517-1G>A
LRG_511t2:c.517-1G>A
LRG_511:g.57038G>A
NC_000022.10:g.30051582G>A
NM_000268.3:c.517-1G>A

Links:

dbSNP: rs1064796632

NCBI 1000 Genomes Browser:

rs1064796632

Molecular consequence:

NM_181833.3:c.447+13308G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000268.4:c.517-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407053.1:c.403-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407054.1:c.394-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407055.1:c.391-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407056.1:c.403-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407057.1:c.517-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407058.1:c.394-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407059.1:c.517-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407060.1:c.517-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407062.1:c.394-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407063.1:c.268-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407064.1:c.268-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407065.1:c.-18-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407066.1:c.517-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001407067.1:c.286-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_016418.5:c.517-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_181825.3:c.517-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_181828.3:c.391-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_181829.3:c.394-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_181830.3:c.268-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_181831.3:c.268-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_181832.3:c.517-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV001373493	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 15, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16199547, 9643284, 16983642, 28492532
SCV001481184	Baylor Genetics - CSER-TexasKidsCanSeq	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 18, 2020)	maternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002045421	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002761909	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 8, 2022)	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	yes	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
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	maternal	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Genotype/phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations.

Evans DG, Trueman L, Wallace A, Collins S, Strachan T.

J Med Genet. 1998 Jun;35(6):450-5. Erratum in: J Med Genet 1999 Jan;36(1):87.

PubMed [citation]

PMID:: 9643284
PMCID:: PMC1051337

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV001373493.5

#	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 affects an acceptor splice site in intron 5 of the NF2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with neurofibromatosis type 2 in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 423789). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NF2 are known to be pathogenic (PMID: 9643284, 16983642). For these reasons, this variant has been classified as Pathogenic.

#	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 Baylor Genetics - CSER-TexasKidsCanSeq, SCV001481184.2

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

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

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

From Genome-Nilou Lab, SCV002045421.1

#	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 Genetics and Molecular Pathology, SA Pathology, SCV002761909.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 20, 2024

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