ClinVar Genomic variation as it relates to human health
NM_000268.4(NF2):c.586C>T (p.Arg196Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000268.4(NF2):c.586C>T (p.Arg196Ter)
Variation ID: 457921 Accession: VCV000457921.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q12.2 22: 29655663 (GRCh38) [ NCBI UCSC ] 22: 30051652 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 2, 2018 Feb 20, 2024 Dec 31, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000268.4:c.586C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000259.1:p.Arg196Ter nonsense NM_016418.5:c.586C>T NP_057502.2:p.Arg196Ter nonsense NM_181825.3:c.586C>T NP_861546.1:p.Arg196Ter nonsense NM_181828.3:c.460C>T NP_861966.1:p.Arg154Ter nonsense NM_181829.3:c.463C>T NP_861967.1:p.Arg155Ter nonsense NM_181830.3:c.337C>T NP_861968.1:p.Arg113Ter nonsense NM_181831.3:c.337C>T NP_861969.1:p.Arg113Ter nonsense NM_181832.3:c.586C>T NP_861970.1:p.Arg196Ter nonsense NM_181833.3:c.447+13378C>T intron variant NR_156186.2:n.1068C>T non-coding transcript variant NC_000022.11:g.29655663C>T NC_000022.10:g.30051652C>T NG_009057.1:g.57108C>T LRG_511:g.57108C>T LRG_511t1:c.586C>T LRG_511p1:p.Arg196Ter LRG_511t2:c.586C>T LRG_511p2:p.Arg196Ter - Protein change
- R196*, R113*, R154*, R155*
- Other names
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- Canonical SPDI
- NC_000022.11:29655662:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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NF2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1944 | 1993 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Dec 31, 2023 | RCV000554782.13 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 2, 2020 | RCV000599281.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 13, 2021 | RCV002358461.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Nov 07, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000709957.2
First in ClinVar: Apr 02, 2018 Last updated: Apr 17, 2019 |
Comment:
The R196X nonsense variant in the NF2 gene has been reported previously in individuals diagnosed with or suspicious for neurofibromatosis type 2 (Joachim et al., … (more)
The R196X nonsense variant in the NF2 gene has been reported previously in individuals diagnosed with or suspicious for neurofibromatosis type 2 (Joachim et al., 2001; Caltabiano et al., 2017). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R196X variant is not observed in large population cohorts (Lek et al., 2016). Based on currently available evidence, we consider R196X to be pathogenic. (less)
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Pathogenic
(Jul 03, 2018)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 2
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917898.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: NF2 c.586C>T (p.Arg196X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: NF2 c.586C>T (p.Arg196X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 246252 control chromosomes (gnomAD). The variant, c.586C>T, has been reported in the literature in multiple individuals affected with Neurofibromatosis Type 2 (Bonne_2016, Bourn_1995, Evans_1998). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 2
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001141389.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(Jun 02, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV001475232.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one … (more)
The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. (less)
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Pathogenic
(Nov 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 2
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002045422.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
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Pathogenic
(Apr 13, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002652675.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R196* pathogenic mutation (also known as c.586C>T), located in coding exon 6 of the NF2 gene, results from a C to T substitution at … (more)
The p.R196* pathogenic mutation (also known as c.586C>T), located in coding exon 6 of the NF2 gene, results from a C to T substitution at nucleotide position 586. This changes the amino acid from an arginine to a stop codon within coding exon 6. This alteration has been reported in numerous individuals with a clinical diagnosis of neurofibromatosis type 2 (Bourn D et al. Hum Genet. 1995 May;95:572-4; MacCollin M et al. Ann Neurol. 1996 Sep;40:440-5; Kluwe L et al. Neurogenetics. 2000 Sep;3:17-24; Evans DG et al. J Neurosurg. 2008 Jan;108:92-6; Plotkin SR et al. J Neurosurg Spine. 2011 Apr;14:543-7; Bonne N- et al. Childs Nerv Syst. 2016 Dec;32:2403-2413; Caltabiano R et al. Childs Nerv Syst. 2017 Jun;33:933-940; Waisberg V et al. Graefes Arch Clin Exp Ophthalmol. 2019 Jul;257:1453-1458). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jul 31, 2019)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761579.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Dec 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000628875.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg196*) in the NF2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg196*) in the NF2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF2 are known to be pathogenic (PMID: 9643284, 16983642). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 2 (PMID: 7759081, 8797533, 11085592, 18033041). ClinVar contains an entry for this variant (Variation ID: 457921). For these reasons, this variant has been classified as Pathogenic. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Ocular alterations, molecular findings, and three novel pathological mutations in a series of NF2 patients. | Waisberg V | Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie | 2019 | PMID: 31089872 |
A mosaic pattern of INI1/SMARCB1 protein expression distinguishes Schwannomatosis and NF2-associated peripheral schwannomas from solitary peripheral schwannomas and NF2-associated vestibular schwannomas. | Caltabiano R | Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery | 2017 | PMID: 28365909 |
Pediatric neurofibromatosis type 2: clinical and molecular presentation, management of vestibular schwannomas, and hearing rehabilitation. | Bonne N- | Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery | 2016 | PMID: 27704245 |
Spinal ependymomas in neurofibromatosis Type 2: a retrospective analysis of 55 patients. | Plotkin SR | Journal of neurosurgery. Spine | 2011 | PMID: 21294614 |
What are the implications in individuals with unilateral vestibular schwannoma and other neurogenic tumors? | Evans DG | Journal of neurosurgery | 2008 | PMID: 18173316 |
[Phenotype-genotype study in 154 French NF2 mutation carriers]. | Demange L | Revue neurologique | 2007 | PMID: 18033041 |
Mutational spectrum of the NF2 gene: a meta-analysis of 12 years of research and diagnostic laboratory findings. | Ahronowitz I | Human mutation | 2007 | PMID: 16983642 |
Somatic mosaicism in neurofibromatosis 2: prevalence and risk of disease transmission to offspring. | Moyhuddin A | Journal of medical genetics | 2003 | PMID: 12807969 |
Molecular study of frequency of mosaicism in neurofibromatosis 2 patients with bilateral vestibular schwannomas. | Kluwe L | Journal of medical genetics | 2003 | PMID: 12566519 |
The parental origin of new mutations in neurofibromatosis 2. | Kluwe L | Neurogenetics | 2000 | PMID: 11085592 |
Genotype/phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations. | Evans DG | Journal of medical genetics | 1998 | PMID: 9643284 |
A point mutation associated with a severe phenotype of neurofibromatosis 2. | MacCollin M | Annals of neurology | 1996 | PMID: 8797533 |
Eleven novel mutations in the NF2 tumour suppressor gene. | Bourn D | Human genetics | 1995 | PMID: 7759081 |
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Text-mined citations for rs1555993336 ...
HelpRecord last updated Feb 28, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.