ClinVar Genomic variation as it relates to human health
NM_000268.4(NF2):c.592C>T (p.Arg198Ter)
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.592C>T (p.Arg198Ter)
Variation ID: 457922 Accession: VCV000457922.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q12.2 22: 29655669 (GRCh38) [ NCBI UCSC ] 22: 30051658 (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 Jul 7, 2018 Feb 14, 2024 Dec 12, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000268.4:c.592C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000259.1:p.Arg198Ter nonsense NM_016418.5:c.592C>T NP_057502.2:p.Arg198Ter nonsense NM_181825.3:c.592C>T NP_861546.1:p.Arg198Ter nonsense NM_181828.3:c.466C>T NP_861966.1:p.Arg156Ter nonsense NM_181829.3:c.469C>T NP_861967.1:p.Arg157Ter nonsense NM_181830.3:c.343C>T NP_861968.1:p.Arg115Ter nonsense NM_181831.3:c.343C>T NP_861969.1:p.Arg115Ter nonsense NM_181832.3:c.592C>T NP_861970.1:p.Arg198Ter nonsense NM_181833.3:c.447+13384C>T intron variant NR_156186.2:n.1074C>T non-coding transcript variant NC_000022.11:g.29655669C>T NC_000022.10:g.30051658C>T NG_009057.1:g.57114C>T LRG_511:g.57114C>T LRG_511t1:c.592C>T LRG_511p1:p.Arg198Ter LRG_511t2:c.592C>T LRG_511p2:p.Arg198Ter - Protein change
- R198*, R156*, R115*, R157*
- Other names
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- Canonical SPDI
- NC_000022.11:29655668: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
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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 |
1946 | - |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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 (4) |
criteria provided, multiple submitters, no conflicts
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Dec 12, 2023 | RCV000533078.10 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 14, 2023 | RCV000712410.5 |
Submissions - Germline
Classification
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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 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 2
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000782125.1
First in ClinVar: Jul 07, 2018 Last updated: Jul 07, 2018 |
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Pathogenic
(Jun 25, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics Inc
Accession: SCV000842900.1
First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018 |
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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: SCV002045423.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
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Pathogenic
(Feb 02, 2022)
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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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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002769046.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurofibromatosis, type 2 (MIM#101000). Somatic variants resulting in the loss of the second allele contribute to meningioma, NF2-related (MIM#607174) and schwannomatosis (MIM#162091). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic in individuals with neurofibromatosis, with or without meningiomas and schwannomas (DECIPHER, PMID: 29409008). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and observed in at least four individuals with neurofibromatosis (PMID: 29409008). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Aug 14, 2023)
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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: SCV001788027.2
First in ClinVar: Aug 21, 2021 Last updated: Aug 24, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18670066, 25525159, 26066488, 7711726, 21294614, 18554169, 10771486, 11275983, 19148485, 29409008, 33067351, 36599646, 24815379) (less)
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Pathogenic
(Dec 12, 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: SCV000628876.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg198*) 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.Arg198*) 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 individuals with neurofibromatosis type 2 (PMID: 7711726, 18033041, 18670066, 24815379, 26066488; Invitae). ClinVar contains an entry for this variant (Variation ID: 457922). 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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Targeted next-generation sequencing for differential diagnosis of neurofibromatosis type 2, schwannomatosis, and meningiomatosis. | Louvrier C | Neuro-oncology | 2018 | PMID: 29409008 |
A Systematic Assessment of Accuracy in Detecting Somatic Mosaic Variants by Deep Amplicon Sequencing: Application to NF2 Gene. | Contini E | PloS one | 2015 | PMID: 26066488 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
Application of COLD-PCR for improved detection of NF2 mosaic mutations. | Paganini I | The Journal of molecular diagnostics : JMD | 2014 | PMID: 24815379 |
Identification of mutations in the NF2 gene in Polish patients with neurofibromatosis type 2. | Łaniewski-Wołłk M | Journal of applied genetics | 2008 | PMID: 18670066 |
[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 |
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 |
High frequency of nonsense mutations in the NF2 gene caused by C to T transitions in five CGA codons. | Sainz J | Human molecular genetics | 1995 | PMID: 7711726 |
Text-mined citations for rs1555993345 ...
HelpRecord last updated Feb 20, 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.