VCV000635820.13 - ClinVar

NM_001042492.3(NF1):c.7063-2A>G

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.

(7)

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.7063-2A>G

Variation ID: 635820 Accession: VCV000635820.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q11.2 17: 31343007 (GRCh38) [ NCBI UCSC ] 17: 29670025 (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 19, 2019	Jun 9, 2024	Dec 28, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001042492.3:c.7063-2A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_000267.3:c.7000-2A>G		splice acceptor
NC_000017.11:g.31343007A>G
NC_000017.10:g.29670025A>G
NG_009018.1:g.253031A>G
LRG_214:g.253031A>G
LRG_214t1:c.7000-2A>G
LRG_214t2:c.7063-2A>G

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000017.11:31343006:A:G

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

sequence_variant_affecting_splicing; Sequence Ontology [ SO:1000071]

Intron inclusion between exons 47 & 48, based on review of RNA-seq in TCGA-22-5472-01A tumor which has NF1 NM_001042492.3:c.7063-2A>G variant [submitted by MutSpliceDB: a database of splice sites variants effects on splicing, NIH]

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

dbSNP: rs1597851255 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	14121	14559

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.
Neurofibroma	Pathogenic (1)	no assertion criteria provided	Jun 29, 2019	RCV000787331.2
Neurofibromatosis, type 1	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Dec 28, 2023	RCV001055190.10
Cardiovascular phenotype Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Apr 27, 2023	RCV002360904.3
not provided	Pathogenic (2)	criteria provided, single submitter	Apr 10, 2023	RCV003166074.1

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 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 (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: SCV001479215.1 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: SCV002560230.1 First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022
Pathogenic (Dec 28, 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: SCV001219566.4 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 16199547‚ 10712197‚ 23913538‚ 16944272‚ 31533651 Comment: This sequence change affects an acceptor splice site in intron 46 of the NF1 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more) This sequence change affects an acceptor splice site in intron 46 of the NF1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 16944272, 23913538, 31533651; Invitae). ClinVar contains an entry for this variant (Variation ID: 635820). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Apr 27, 2023)	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: SCV002666627.2 First in ClinVar: Nov 29, 2022 Last updated: Jun 09, 2024	Comment: The c.7000-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 47 in the NF1 gene. This mutation … (more) The c.7000-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 47 in the NF1 gene. This mutation has been detected in individuals with a clinical or suspected diagnosis of neurofibromatosis type 1 (Griffiths S et al. Fam. Cancer, 2007;6:21-34; Sabbagh A et al. Hum. Mutat., 2013 Nov;34:1510-8; Ambry internal data). In RNA studies, this variant resulted in skipping of exon 47 and insertion of partial intron 46 (Sabbagh A et al. Hum. Mutat., 2013 Nov;34:1510-8; Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. (less)
Pathogenic (Apr 10, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003915409.1 First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023	Comment: Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease … (more) Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease (Sabbagh et al., 2013); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23913538, 16944272, 31533651) (less)
Pathogenic (Jun 29, 2019)	no assertion criteria provided Method: clinical testing	Neurofibroma Affected status: yes Allele origin: germline	Department of Ophthalmology, Shanghai Ninth people hospital, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University Accession: SCV000926273.1 First in ClinVar: Jul 19, 2019 Last updated: Jul 19, 2019	Age: 0-9 years Sex: female Ethnicity/Population group: Chinese Han Geographic origin: China
not provided (-)	no classification provided Method: research	not provided Affected status: not applicable Allele origin: somatic	MutSpliceDB: a database of splice sites variants effects on splicing, NIH Accession: SCV004037028.1 First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023	Other databases https://brb.nci.nih.gov/cgi-bin/… https://brb.nci.nih.gov/cgi-bin/splicing/splicing_evidence.cgi?caid=CA399015494 Comment on evidence: Intron inclusion between exons 47 & 48, based on review of RNA-seq in TCGA-22-5472-01A tumor which has NF1 NM_001042492.3:c.7063-2A>G variant Result: Intron inclusion between exons 47 & 48

Comment:

This sequence change affects an acceptor splice site in intron 46 of the NF1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 16944272, 23913538, 31533651; Invitae). ClinVar contains an entry for this variant (Variation ID: 635820). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.7000-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 47 in the NF1 gene. This mutation has been detected in individuals with a clinical or suspected diagnosis of neurofibromatosis type 1 (Griffiths S et al. Fam. Cancer, 2007;6:21-34; Sabbagh A et al. Hum. Mutat., 2013 Nov;34:1510-8; Ambry internal data). In RNA studies, this variant resulted in skipping of exon 47 and insertion of partial intron 46 (Sabbagh A et al. Hum. Mutat., 2013 Nov;34:1510-8; Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.

Comment:

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease (Sabbagh et al., 2013); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23913538, 16944272, 31533651)

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
sequence_variant_affecting_splicing (SO:1000071)	Method not provided	Intron inclusion between exons 47 & 48	MutSpliceDB: a database of splice sites variants effects on splicing, NIH Accession: SCV004037028.1	Other databases https://brb.nci.nih.gov/cgi-bin/… Comment: Intron inclusion between exons 47 & 48, based on review of RNA-seq in TCGA-22-5472-01A tumor which has NF1 NM_001042492.3:c.7063-2A>G variant

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical characteristics and mutation Spectrum of NF1 in 12 Chinese families with orbital/periorbital plexiform Neurofibromatosis type 1.	Chai P	BMC medical genetics	2019	PMID: 31533651
NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience.	Sabbagh A	Human mutation	2013	PMID: 23913538
Molecular diagnosis of neurofibromatosis type 1: 2 years experience.	Griffiths S	Familial cancer	2007	PMID: 16944272
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
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
https://brb.nci.nih.gov/cgi-bin/splicing/splicing_evidence.cgi?caid=CA399015494	-	-	-	-

Text-mined citations for rs1597851255 ...

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_001042492.3(NF1):c.7063-2A>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1597851255 ...