VCV002568064.3 - ClinVar

NM_000268.4(NF2):c.1652_1655del (p.Leu551fs)

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.

(2)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000268.4(NF2):c.1652_1655del (p.Leu551fs)

Variation ID: 2568064 Accession: VCV002568064.3

Type and length

Deletion, 4 bp

Location

Cytogenetic: 22q12.2 22: 29681516-29681519 (GRCh38) [ NCBI UCSC ] 22: 30077505-30077508 (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 8, 2023	May 1, 2024	Dec 18, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000268.4:c.1652_1655del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000259.1:p.Leu551fs	frameshift
NM_001407053.1:c.1538_1541del	NP_001393982.1:p.Leu513fs	frameshift
NM_001407054.1:c.1529_1532del	NP_001393983.1:p.Leu510fs	frameshift
NM_001407055.1:c.1526_1529del	NP_001393984.1:p.Leu509fs	frameshift
NM_001407056.1:c.1538_1541del	NP_001393985.1:p.Leu513fs	frameshift
NM_001407057.1:c.1517_1520del	NP_001393986.1:p.Leu506fs	frameshift
NM_001407058.1:c.1529_1532del	NP_001393987.1:p.Leu510fs	frameshift
NM_001407059.1:c.1517_1520del	NP_001393988.1:p.Leu506fs	frameshift
NM_001407060.1:c.1574+3193_1574+3196del		intron variant
NM_001407062.1:c.1394_1397del	NP_001393991.1:p.Leu465fs	frameshift
NM_001407063.1:c.1403_1406del	NP_001393992.1:p.Leu468fs	frameshift
NM_001407064.1:c.1325+3193_1325+3196del		intron variant
NM_001407065.1:c.1118_1121del	NP_001393994.1:p.Leu373fs	frameshift
NM_001407066.1:c.1652_1655del	NP_001393995.1:p.Leu551fs	frameshift
NM_001407067.1:c.1421_1424del	NP_001393996.1:p.Leu474fs	frameshift
NM_016418.5:c.1652_1655del	NP_057502.2:p.Leu551fs	frameshift
NM_181825.3:c.1652_1655del	NP_861546.1:p.Leu551fs	frameshift
NM_181828.3:c.1526_1529del	NP_861966.1:p.Leu509fs	frameshift
NM_181829.3:c.1529_1532del	NP_861967.1:p.Leu510fs	frameshift
NM_181830.3:c.1403_1406del	NP_861968.1:p.Leu468fs	frameshift
NM_181831.3:c.1403_1406del	NP_861969.1:p.Leu468fs	frameshift
NM_181832.3:c.1652_1655del	NP_861970.1:p.Leu551fs	frameshift
NM_181833.3:c.448-13236_448-13233del		intron variant
NR_156186.2:n.2134_2137delTGAA
NC_000022.11:g.29681516_29681519del
NC_000022.10:g.30077505_30077508del
NG_009057.1:g.82961_82964del
LRG_511:g.82961_82964del
LRG_511t1:c.1652_1655del	LRG_511p1:p.Leu551Glnfs
LRG_511t2:c.1652_1655del	LRG_511p2:p.Leu551fs

... more HGVS ... less HGVS

Protein change

L468fs, L506fs, L509fs, L551fs, L373fs, L465fs, L513fs, L510fs, L474fs

Other names

Canonical SPDI

NC_000022.11:29681515:TGAA:

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.

Links

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.
Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	May 16, 2023	RCV003297518.2
Neurofibromatosis, type 2	Uncertain significance (1)	criteria provided, single submitter	Dec 18, 2023	RCV004009726.2

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 (Dec 18, 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: SCV004838379.1 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 variant deletes 4 nucleotides in exon 15 of the NF2 gene, causing a frameshift and addition of 1 new amino acid before introducing a … (more) This variant deletes 4 nucleotides in exon 15 of the NF2 gene, causing a frameshift and addition of 1 new amino acid before introducing a stop codon. This results in a protein product that is 1 amino acid longer than the normal protein product. To our knowledge, functional studies have not been reported for this variant. To our knowledge, this variant has not been reported in individuals affected with NF2-related disorders 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
Uncertain significance (May 16, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV004007042.2 First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024	Comment: The c.1652_1655delTGAA variant, located in coding exon 15 of the NF2 gene, results from a deletion of 4 nucleotides at nucleotide positions 1652 to 1655, … (more) The c.1652_1655delTGAA variant, located in coding exon 15 of the NF2 gene, results from a deletion of 4 nucleotides at nucleotide positions 1652 to 1655, causing a translational frameshift with a predicted alternate stop codon (p.L551Qfs*47). This alteration occurs at the 3' terminus of theNF2 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 7.5% of the protein. The exact functional effect of this alteration is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

This variant deletes 4 nucleotides in exon 15 of the NF2 gene, causing a frameshift and addition of 1 new amino acid before introducing a stop codon. This results in a protein product that is 1 amino acid longer than the normal protein product. To our knowledge, functional studies have not been reported for this variant. To our knowledge, this variant has not been reported in individuals affected with NF2-related disorders 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.

Comment:

The c.1652_1655delTGAA variant, located in coding exon 15 of the NF2 gene, results from a deletion of 4 nucleotides at nucleotide positions 1652 to 1655, causing a translational frameshift with a predicted alternate stop codon (p.L551Qfs*47). This alteration occurs at the 3' terminus of theNF2 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 7.5% of the protein. The exact functional effect of this alteration is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated May 08, 2024

ClinVar Genomic variation as it relates to human health

NM_000268.4(NF2):c.1652_1655del (p.Leu551fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...