VCV002921216.1 - ClinVar

NM_001042492.3(NF1):c.2251+2T>C

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.

(1)

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, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001042492.3(NF1):c.2251+2T>C

Variation ID: 2921216 Accession: VCV002921216.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q11.2 17: 31226686 (GRCh38) [ NCBI UCSC ] 17: 29553704 (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 20, 2024	Feb 20, 2024	Sep 12, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001042492.3:c.2251+2T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_000267.3:c.2251+2T>C		splice donor
NC_000017.11:g.31226686T>C
NC_000017.10:g.29553704T>C
NG_009018.1:g.136710T>C
LRG_214:g.136710T>C
LRG_214t1:c.2251+2T>C

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000017.11:31226685:T:C

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.
NF1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	14106	14543

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.
not provided	Pathogenic (1)	criteria provided, single submitter	Sep 12, 2023	RCV003740629.1

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 (Sep 12, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV004563776.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Comment: The NF1 c.2251+2T>C variant, also published as IVS13+2T>C, is reported in the literature in several individuals affected with neurofibromatosis type 1 (Pros 2008, Serra 2001). … (more) The NF1 c.2251+2T>C variant, also published as IVS13+2T>C, is reported in the literature in several individuals affected with neurofibromatosis type 1 (Pros 2008, Serra 2001). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 18 (also published as intron 13), which is likely to negatively impact gene function. Indeed, cDNA analysis in patient fibroblasts suggests this variants results in exon skipping and a frameshift (Pros 2008). Based on available information, this variant is considered to be pathogenic. References: Pros E et al. Nature and mRNA effect of 282 different NF1 point mutations: focus on splicing alterations. Hum Mutat. 2008 Sep;29(9):E173-93. PMID: 18546366. Serra E et al. Somatic NF1 mutational spectrum in benign neurofibromas: mRNA splice defects are common among point mutations. Hum Genet. 2001 May;108(5):416-29. PMID: 11409870. (less)

Comment:

The NF1 c.2251+2T>C variant, also published as IVS13+2T>C, is reported in the literature in several individuals affected with neurofibromatosis type 1 (Pros 2008, Serra 2001). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 18 (also published as intron 13), which is likely to negatively impact gene function. Indeed, cDNA analysis in patient fibroblasts suggests this variants results in exon skipping and a frameshift (Pros 2008). Based on available information, this variant is considered to be pathogenic. References: Pros E et al. Nature and mRNA effect of 282 different NF1 point mutations: focus on splicing alterations. Hum Mutat. 2008 Sep;29(9):E173-93. PMID: 18546366. Serra E et al. Somatic NF1 mutational spectrum in benign neurofibromas: mRNA splice defects are common among point mutations. Hum Genet. 2001 May;108(5):416-29. PMID: 11409870.

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 Feb 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001042492.3(NF1):c.2251+2T>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...