ClinVar Genomic variation as it relates to human health
NM_000268.4(NF2):c.1055C>T (p.Thr352Met)
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.1055C>T (p.Thr352Met)
Variation ID: 569661 Accession: VCV000569661.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q12.2 22: 29671881 (GRCh38) [ NCBI UCSC ] 22: 30067870 (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 Oct 10, 2018 Aug 11, 2024 Apr 12, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000268.4:c.1055C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000259.1:p.Thr352Met missense NM_016418.5:c.1055C>T NP_057502.2:p.Thr352Met missense NM_181825.3:c.1055C>T NP_861546.1:p.Thr352Met missense NM_181828.3:c.929C>T NP_861966.1:p.Thr310Met missense NM_181829.3:c.932C>T NP_861967.1:p.Thr311Met missense NM_181830.3:c.806C>T NP_861968.1:p.Thr269Met missense NM_181831.3:c.806C>T NP_861969.1:p.Thr269Met missense NM_181832.3:c.1055C>T NP_861970.1:p.Thr352Met missense NM_181833.3:c.448-22871C>T intron variant NR_156186.2:n.1537C>T non-coding transcript variant NC_000022.11:g.29671881C>T NC_000022.10:g.30067870C>T NG_009057.1:g.73326C>T LRG_511:g.73326C>T LRG_511t1:c.1055C>T LRG_511p1:p.Thr352Met LRG_511t2:c.1055C>T LRG_511p2:p.Thr352Met - Protein change
- T352M, T269M, T310M, T311M
- Other names
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- Canonical SPDI
- NC_000022.11:29671880: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.
The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
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 |
2081 | 2129 |
Conditions - Germline
Condition
Help
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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Dec 2, 2023 | RCV000690349.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 12, 2024 | RCV002406553.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 24, 2024 | RCV004569293.1 |
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
Help
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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Uncertain significance
(Dec 02, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000818031.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 352 of the NF2 protein (p.Thr352Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 352 of the NF2 protein (p.Thr352Met). This variant is present in population databases (rs764441073, gnomAD 0.003%). This missense change has been observed in individual(s) with neurofibromatosis type 2 (NF2), osteosarcoma, as well as unaffected individuals (PMID: 8081368, 32191290; Invitae). ClinVar contains an entry for this variant (Variation ID: 569661). 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%. Experimental studies have shown that this missense change affects NF2 function (PMID: 10712203, 11779178). 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. (less)
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Uncertain Significance
(Nov 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004821914.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces threonine with methionine at codon 352 of the NF2 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces threonine with methionine at codon 352 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). Functional studies have reported that the variant protein behaved similar to wild-type protein expressed in ex vivo cultured cells in protein expression, protein-protein interaction, subcellular localization, cell proliferation and actin cytoskeleton associated activity assays (PMID: 10712203, 11448944). This variant has been reported in an individual affected with type 2 neurofibromatosis (PMID: 8081368). This variant has been identified in 3/251460 chromosomes 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. (less)
Number of individuals with the variant: 3
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Uncertain significance
(Mar 24, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial meningioma
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV005052360.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Uncertain significance
(Apr 12, 2024)
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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: SCV002715516.4
First in ClinVar: Nov 29, 2022 Last updated: Aug 11, 2024 |
Comment:
The p.T352M variant (also known as c.1055C>T), located in coding exon 11 of the NF2 gene, results from a C to T substitution at nucleotide … (more)
The p.T352M variant (also known as c.1055C>T), located in coding exon 11 of the NF2 gene, results from a C to T substitution at nucleotide position 1055. The threonine at codon 352 is replaced by methionine, an amino acid with similar properties. The variant has been reported to be de novo in one individual with neurofibromatosis 2 (NF2) and detected in another individual with bilateral vestibular schwannomas (Evans DG et al. J Med Genet, 1992 Dec;29:841-6; Bourn D et al. Hum. Mol. Genet., 1994 May;3:813-6). However, this variant has been identified in multiple individuals without clinical features of NF2 (Ambry internal data). Functional studies have shown that the variant may affect some aspects of the NF2 protein function; however, most of the functions are unaffected and clinical relevance of these studies is unknown (Stokowski RP et al. Am J Hum Genet, 2000 Mar;66:873-91; Gutmann DH et al. Hum Mol Genet, 2001 Jul;10:1519-29; Scoles DR et al. Biochem Biophys Res Commun, 2002 Jan;290:366-74). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. (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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Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in Patients With Osteosarcoma. | Mirabello L | JAMA oncology | 2020 | PMID: 32191290 |
Effects of Nf2 missense mutations on schwannomin interactions. | Scoles DR | Biochemical and biophysical research communications | 2002 | PMID: 11779178 |
Functional analysis of neurofibromatosis 2 (NF2) missense mutations. | Gutmann DH | Human molecular genetics | 2001 | PMID: 11448944 |
Functional analysis of the neurofibromatosis type 2 protein by means of disease-causing point mutations. | Stokowski RP | American journal of human genetics | 2000 | PMID: 10712203 |
Germline mutations in the neurofibromatosis type 2 tumour suppressor gene. | Bourn D | Human molecular genetics | 1994 | PMID: 8081368 |
A genetic study of type 2 neurofibromatosis in the United Kingdom. I. Prevalence, mutation rate, fitness, and confirmation of maternal transmission effect on severity. | Evans DG | Journal of medical genetics | 1992 | PMID: 1479598 |
Text-mined citations for rs764441073 ...
HelpRecord last updated Sep 29, 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.