VCV000404591.15 - ClinVar

NM_001042492.3(NF1):c.288+1del

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.

(6)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001042492.3(NF1):c.288+1del

Variation ID: 404591 Accession: VCV000404591.15

Type and length

Deletion, 1 bp

Location

Cytogenetic: 17q11.2 17: 31159091 (GRCh38) [ NCBI UCSC ] 17: 29486109 (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	Feb 10, 2017	Nov 17, 2024	Nov 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001042492.3:c.288+1del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_000267.3:c.288+1del		splice donor
NM_000267.3:c.288+1delG		splice donor
NM_001128147.3:c.288+1del		splice donor
NC_000017.11:g.31159094del
NC_000017.10:g.29486112del
NG_009018.1:g.69115delG
NG_009018.1:g.69118del
LRG_214:g.69118del
LRG_214t1:c.288+1del

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000017.11:31159090:GGGG:GGG

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

ClinGen: CA16044136 dbSNP: rs1057519370 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.
NF1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	14135	14574

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 1	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Apr 23, 2023	RCV000472465.20
Cardiovascular phenotype Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Jan 5, 2024	RCV004559071.1
not provided	Pathogenic (1)	criteria provided, single submitter	Nov 5, 2024	RCV004701488.2

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.
Pathogenic (Feb 02, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Neurofibromatosis, type 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Department of Research and Development, Institute Hermes Pardini Accession: SCV000264657.1 First in ClinVar: Feb 10, 2017 Last updated: Feb 10, 2017	Comment: PVS1 - disrupt gene (frameshift), PM2 - Absent in population databases, PM4 - Protein lenght change, PP3 - Multiple deleterious effect and PP4 - Patient's … (more) PVS1 - disrupt gene (frameshift), PM2 - Absent in population databases, PM4 - Protein lenght change, PP3 - Multiple deleterious effect and PP4 - Patient's phenotype (less) Number of individuals with the variant: 1 Clinical Features: Plexiform neurofibroma (present) , Inguinal freckling (present) , Neurofibrosarcoma (present) , Autosomal dominant inheritance (present) , Short stature (present) , Café-au-lait spot (present) , Axillary … (more) Plexiform neurofibroma (present) , Inguinal freckling (present) , Neurofibrosarcoma (present) , Autosomal dominant inheritance (present) , Short stature (present) , Café-au-lait spot (present) , Axillary freckling (present) (less)
Pathogenic (Oct 26, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 1 Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV001479126.1 First in ClinVar: Feb 13, 2021 Last updated: Feb 13, 2021
Pathogenic (Mar 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 1 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002561565.1 First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022
Pathogenic (Apr 23, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Neurofibromatosis, type 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000542201.6 First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024	Publications: PubMed (5) PubMed: 19221814‚ 30308447‚ 31730495‚ 10712197‚ 23913538 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 404591). This premature translational stop signal … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 404591). This premature translational stop signal has been observed in individual(s) with neurofibromatosis (PMID: 19221814, 30308447, 31730495). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (Splice site) in the NF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). (less)
Pathogenic (Jan 05, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Hereditary cancer-predisposing syndrome Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005047632.1 First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024	Comment: The c.288+1delG intronic variant, located in intron 3 of the NF1 gene, results from a deletion of one nucleotide within intron 3 of the NF1 … (more) The c.288+1delG intronic variant, located in intron 3 of the NF1 gene, results from a deletion of one nucleotide within intron 3 of the NF1 gene. This variant was reported in multiple individuals with features consistent with neurofibromatosis type 1 (NF1) or individuals who met clinical criteria for NF1 (Upadhyaya M et al. Neurogenetics, 2009 Jul;10:251-63; Tsipi M et al. J Neurol Sci, 2018 Dec;395:95-105; Giugliano T et al. Genes (Basel), 2019 Jul;10:;Assunto A et al. Orphanet J Rare Dis, 2019 Nov;14:261; Byrjalsen A et al. PLoS Genet, 2020 Dec;16:e1009231). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Nov 05, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005202025.2 First in ClinVar: Sep 16, 2024 Last updated: Nov 17, 2024	Comment: Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a … (more) Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.288delG; This variant is associated with the following publications: (PMID: 22155606, 33332384, 34308104, 36612057, 10712197, 23913538, 30308447, 31730495, 19221814, 31370276) (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 404591). This premature translational stop signal has been observed in individual(s) with neurofibromatosis (PMID: 19221814, 30308447, 31730495). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (Splice site) in the NF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538).

Comment:

The c.288+1delG intronic variant, located in intron 3 of the NF1 gene, results from a deletion of one nucleotide within intron 3 of the NF1 gene. This variant was reported in multiple individuals with features consistent with neurofibromatosis type 1 (NF1) or individuals who met clinical criteria for NF1 (Upadhyaya M et al. Neurogenetics, 2009 Jul;10:251-63; Tsipi M et al. J Neurol Sci, 2018 Dec;395:95-105; Giugliano T et al. Genes (Basel), 2019 Jul;10:;Assunto A et al. Orphanet J Rare Dis, 2019 Nov;14:261; Byrjalsen A et al. PLoS Genet, 2020 Dec;16:e1009231). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Comment:

Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.288delG; This variant is associated with the following publications: (PMID: 22155606, 33332384, 34308104, 36612057, 10712197, 23913538, 30308447, 31730495, 19221814, 31370276)

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
Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1.	Assunto A	Orphanet journal of rare diseases	2019	PMID: 31730495
Phenotypic expression of a spectrum of Neurofibromatosis Type 1 (NF1) mutations identified through NGS and MLPA.	Tsipi M	Journal of the neurological sciences	2018	PMID: 30308447
NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience.	Sabbagh A	Human mutation	2013	PMID: 23913538
The spectrum of somatic and germline NF1 mutations in NF1 patients with spinal neurofibromas.	Upadhyaya M	Neurogenetics	2009	PMID: 19221814
Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain.	Fahsold R	American journal of human genetics	2000	PMID: 10712197

Text-mined citations for rs1057519370 ...

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 Nov 30, 2024

ClinVar Genomic variation as it relates to human health

NM_001042492.3(NF1):c.288+1del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1057519370 ...