Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 2 or 3 probands
ClinVar Genomic variation as it relates to human health
NM_000268.4(NF2):c.613A>G (p.Met205Val)
Germline
Classification
Help
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.
(8)
Help
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.
Conflicting classifications of pathogenicity
Uncertain significance(3); Benign(2); Likely benign(3)
Uncertain significance(3); Benign(2); Likely benign(3)
8
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000268.4(NF2):c.613A>G (p.Met205Val)
Variation ID: 237626 Accession: VCV000237626.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q12.2 22: 29658202 (GRCh38) [ NCBI UCSC ] 22: 30054191 (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 9, 2017 Sep 16, 2024 Feb 5, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000268.4:c.613A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000259.1:p.Met205Val missense NM_016418.5:c.613A>G NP_057502.2:p.Met205Val missense NM_181825.3:c.613A>G NP_861546.1:p.Met205Val missense NM_181828.3:c.487A>G NP_861966.1:p.Met163Val missense NM_181829.3:c.490A>G NP_861967.1:p.Met164Val missense NM_181830.3:c.364A>G NP_861968.1:p.Met122Val missense NM_181831.3:c.364A>G NP_861969.1:p.Met122Val missense NM_181832.3:c.613A>G NP_861970.1:p.Met205Val missense NM_181833.3:c.447+15917A>G intron variant NR_156186.2:n.1095A>G non-coding transcript variant NC_000022.11:g.29658202A>G NC_000022.10:g.30054191A>G NG_009057.1:g.59647A>G LRG_511:g.59647A>G LRG_511t1:c.613A>G LRG_511p1:p.Met205Val LRG_511t2:c.613A>G LRG_511p2:p.Met205Val - Protein change
- M205V, M163V, M122V, M164V
- Other names
- -
- Canonical SPDI
- NC_000022.11:29658201:A:G
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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
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00008
Exome Aggregation Consortium (ExAC) 0.00009
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
The Genome Aggregation Database (gnomAD) 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00017
- 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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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 |
2084 | 2132 | |
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Jan 31, 2024 | RCV000234683.22 | |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Jan 12, 2023 | RCV000455031.9 | |
| Benign (1) |
criteria provided, single submitter
|
May 21, 2021 | RCV000565164.5 | |
| Likely benign (1) |
criteria provided, single submitter
|
Feb 5, 2024 | RCV001706246.3 |
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
Help
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
Help
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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|---|---|---|---|---|---|
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Uncertain significance
(Jun 23, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000539888.1
First in ClinVar: Apr 09, 2017 Last updated: Apr 09, 2017 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 2 or 3 probands (less)
Method: Genome/Exome Filtration
|
|
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Benign
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Neurofibromatosis, type 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000284554.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
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Benign
(May 21, 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
|
Ambry Genetics
Accession: SCV000674134.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
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Likely benign
(Nov 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 2
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002045400.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
|
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Uncertain significance
(Jul 02, 2018)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 2
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV000839515.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
|
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Likely benign
(Jan 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003800705.2
First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023 |
Comment:
Variant summary: NF2 c.613A>G (p.Met205Val) results in a conservative amino acid change located in the FERM domain (IPR000299) of the encoded protein sequence. Four of … (more)
Variant summary: NF2 c.613A>G (p.Met205Val) results in a conservative amino acid change located in the FERM domain (IPR000299) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 282888 control chromosomes (gnomAD), predominantly at a frequency of 0.00018 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 9.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in NF2 causing Neurofibromatosis Type 2 phenotype (1.9e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Six ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance, two as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Uncertain Significance
(Dec 13, 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
|
All of Us Research Program, National Institutes of Health
Accession: SCV004821910.1
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)
|
Comment:
This missense variant replaces methionine with valine at codon 205 of the NF2 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces methionine with valine at codon 205 of the NF2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with multiple meningiomas or Neurofibromatosis type 2 (PMID: 15635074, 26073919). This variant has been identified in 24/282888 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: 30
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Likely benign
(Feb 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001825051.3
First in ClinVar: Sep 26, 2021 Last updated: Sep 16, 2024 |
Comment:
See Variant Classification Assertion Criteria.
|
Comment:
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
Variant summary: NF2 c.613A>G (p.Met205Val) results in a conservative amino acid change located in the FERM domain (IPR000299) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 282888 control chromosomes (gnomAD), predominantly at a frequency of 0.00018 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 9.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in NF2 causing Neurofibromatosis Type 2 phenotype (1.9e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Six ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance, two as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
This missense variant replaces methionine with valine at codon 205 of the NF2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with multiple meningiomas or Neurofibromatosis type 2 (PMID: 15635074, 26073919). This variant has been identified in 24/282888 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.
Comment:
See Variant Classification Assertion Criteria.
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. |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 2 or 3 probands
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
Variant summary: NF2 c.613A>G (p.Met205Val) results in a conservative amino acid change located in the FERM domain (IPR000299) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 282888 control chromosomes (gnomAD), predominantly at a frequency of 0.00018 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 9.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in NF2 causing Neurofibromatosis Type 2 phenotype (1.9e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Six ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance, two as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
This missense variant replaces methionine with valine at codon 205 of the NF2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with multiple meningiomas or Neurofibromatosis type 2 (PMID: 15635074, 26073919). This variant has been identified in 24/282888 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.
Comment:
See Variant Classification Assertion Criteria.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Neurofibromatosis type 2 French cohort analysis using a comprehensive NF2 molecular diagnostic strategy. | Pasmant E | Neuro-Chirurgie | 2018 | PMID: 26073919 |
| 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 |
| Multiple meningiomas: differential involvement of the NF2 gene in children and adults. | Evans DG | Journal of medical genetics | 2005 | PMID: 15635074 |
Text-mined citations for rs141629512 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record 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.