VCV000956856.13 - ClinVar

NM_000268.4(NF2):c.1A>G (p.Met1Val)

Germline

Classification

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.

(5)

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
Pathogenic(1); Uncertain significance(4)

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.1A>G (p.Met1Val)

Variation ID: 956856 Accession: VCV000956856.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q12.2 22: 29603999 (GRCh38) [ NCBI UCSC ] 22: 29999988 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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 16, 2020	Apr 20, 2024	Mar 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000268.4:c.1A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000259.1:p.Met1Val	missense initiator codon variant
NM_016418.5:c.1A>G	NP_057502.2:p.Met1Val	missense initiator codon variant
NM_181825.3:c.1A>G	NP_861546.1:p.Met1Val	missense initiator codon variant
NM_181828.3:c.1A>G	NP_861966.1:p.Met1Val	missense initiator codon variant
NM_181829.3:c.1A>G	NP_861967.1:p.Met1Val	missense initiator codon variant
NM_181830.3:c.1A>G	NP_861968.1:p.Met1Val	missense initiator codon variant
NM_181831.3:c.1A>G	NP_861969.1:p.Met1Val	missense initiator codon variant
NM_181832.3:c.1A>G	NP_861970.1:p.Met1Val	missense initiator codon variant
NM_181833.3:c.1A>G	NP_861971.1:p.Met1Val	missense initiator codon variant
NR_156186.2:n.367A>G		non-coding transcript variant
NC_000022.11:g.29603999A>G
NC_000022.10:g.29999988A>G
NG_009057.1:g.5444A>G
LRG_511:g.5444A>G
LRG_511t1:c.1A>G
LRG_511t2:c.1A>G	LRG_511p2:p.Met1Val

... more HGVS ... less HGVS

Protein change

M1V

Other names

Canonical SPDI

NC_000022.11:29603998:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Links

dbSNP: rs1319282473 VarSome

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
Gene	OMIM	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.
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.
Neurofibromatosis, type 2	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Mar 26, 2024	RCV001229737.12
not provided	Uncertain significance (1)	criteria provided, single submitter	Apr 25, 2019	RCV001751446.2

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.
Uncertain significance (Nov 07, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 2 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002045429.2 First in ClinVar: Jan 03, 2022 Last updated: Sep 03, 2023
Uncertain significance (Feb 11, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Neurofibromatosis, type 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001402192.5 First in ClinVar: Jul 16, 2020 Last updated: Sep 03, 2023	Comment: This sequence change affects the initiator methionine of the NF2 mRNA. The next in-frame methionine is located at codon 9. This variant is not present … (more) This sequence change affects the initiator methionine of the NF2 mRNA. The next in-frame methionine is located at codon 9. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 956856). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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)
Uncertain significance (Apr 25, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001985707.3 First in ClinVar: Nov 06, 2021 Last updated: Sep 03, 2023	Comment: Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; This variant is … (more) Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31130284) (less)
Pathogenic (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 2 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004806815.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Uncertain Significance (Jun 26, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 2 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004821906.1 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)	Publications: PubMed (1) PubMed: 25893302 Comment: This variant results in the loss of the translation initiator methionine at codon 1 of the NF2 protein. The NF2 gene encodes for a methionine … (more) This variant results in the loss of the translation initiator methionine at codon 1 of the NF2 protein. The NF2 gene encodes for a methionine codon 9 before known functional domains (PMID: 25893302) and a second methionine at codon 29. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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: 1

Comment:

This sequence change affects the initiator methionine of the NF2 mRNA. The next in-frame methionine is located at codon 9. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 956856). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.

Comment:

This variant results in the loss of the translation initiator methionine at codon 1 of the NF2 protein. The NF2 gene encodes for a methionine codon 9 before known functional domains (PMID: 25893302) and a second methionine at codon 29. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Role of Merlin/NF2 inactivation in tumor biology.	Petrilli AM	Oncogene	2016	PMID: 25893302

Text-mined citations for rs1319282473 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_000268.4(NF2):c.1A>G (p.Met1Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1319282473 ...