VCV000404571.12 - ClinVar

NM_001042492.3(NF1):c.6921+1G>A

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.6921+1G>A

Variation ID: 404571 Accession: VCV000404571.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q11.2 17: 31338806 (GRCh38) [ NCBI UCSC ] 17: 29665824 (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	Aug 13, 2017	Jun 9, 2024	Aug 6, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001042492.3:c.6921+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_000267.3:c.6858+1G>A		splice donor
NC_000017.11:g.31338806G>A
NC_000017.10:g.29665824G>A
NG_009018.1:g.248830G>A
LRG_214:g.248830G>A
LRG_214t1:c.6858+1G>A
LRG_214t2:c.6921+1G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000017.11:31338805:G:A

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: CA16615312 dbSNP: rs1060500355 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	14115	14552

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 (5)	criteria provided, multiple submitters, no conflicts	Aug 6, 2023	RCV000476980.10
not provided	Pathogenic (1)	criteria provided, single submitter	Mar 11, 2019	RCV001558427.2
Cardiovascular phenotype Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Mar 20, 2019	RCV002374746.2

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 (Apr 02, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 1 Affected status: yes Allele origin: germline	Department of Molecular Diagnostics, Institute of Oncology Ljubljana Accession: SCV001499693.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021
Pathogenic (Mar 11, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001780371.1 First in ClinVar: Aug 13, 2021 Last updated: Aug 13, 2021	Comment: Canonical splice site variant predicted to result in an in-frame deletion of a critical region; Deletions involving coding exons in this gene are frequently reported … (more) Canonical splice site variant predicted to result in an in-frame deletion of a critical region; Deletions involving coding exons in this gene are frequently reported as pathogenic, regardless of frame prediction (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24789688, 24232412, 17120035, 21520333, 11735023, 25525159) (less)
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: SCV002560221.1 First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022
Pathogenic (Aug 06, 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: SCV000542170.6 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024	Publications: PubMed (7) PubMed: 10607834‚ 11735023‚ 11857752‚ 17426081‚ 16199547‚ 10712197‚ 23913538 Comment: Disruption of this splice site has been observed in individuals with neurofibromatosis type 1 (PMID: 10607834, 11735023, 11857752, 17426081). This variant is not present in … (more) Disruption of this splice site has been observed in individuals with neurofibromatosis type 1 (PMID: 10607834, 11735023, 11857752, 17426081). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 45 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). ClinVar contains an entry for this variant (Variation ID: 404571). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. (less)
Pathogenic (Mar 20, 2019)	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: SCV002667583.2 First in ClinVar: Nov 29, 2022 Last updated: Jun 09, 2024	Comment: The c.6858+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 45 of the NF1 gene. This mutation was … (more) The c.6858+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 45 of the NF1 gene. This mutation was identified in an individual with a clinical diagnosis of neurofibromatosis type 1 (Han SS et al. Hum. Genet., 2001 Nov;109:487-97). Two disease-causing mutations, c.6858+1G>T and c.6858+1G>C, have been described at the same position (Kluwe L et al. Hum. Mutat., 2002 Mar;19:309; Wimmer K et al. Hum. Mutat., 2007 Jun;28:599-612). In addition to the clinical data presented in the literature, 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)
Likely pathogenic (Feb 02, 2017)	no assertion criteria provided Method: clinical testing	Neurofibromatosis type 1 Affected status: yes Allele origin: germline	Medical Genetics, University of Parma Accession: SCV000588827.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017
Pathogenic (Dec 13, 2016)	no assertion criteria provided Method: clinical testing	Neurofibromatosis, type 1 Affected status: yes Allele origin: germline	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital Accession: SCV000692364.1 First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018

Comment:

Canonical splice site variant predicted to result in an in-frame deletion of a critical region; Deletions involving coding exons in this gene are frequently reported as pathogenic, regardless of frame prediction (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24789688, 24232412, 17120035, 21520333, 11735023, 25525159)

Comment:

Disruption of this splice site has been observed in individuals with neurofibromatosis type 1 (PMID: 10607834, 11735023, 11857752, 17426081). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 45 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). ClinVar contains an entry for this variant (Variation ID: 404571). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.

Comment:

The c.6858+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 45 of the NF1 gene. This mutation was identified in an individual with a clinical diagnosis of neurofibromatosis type 1 (Han SS et al. Hum. Genet., 2001 Nov;109:487-97). Two disease-causing mutations, c.6858+1G>T and c.6858+1G>C, have been described at the same position (Kluwe L et al. Hum. Mutat., 2002 Mar;19:309; Wimmer K et al. Hum. Mutat., 2007 Jun;28:599-612). In addition to the clinical data presented in the literature, 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.

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
NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience.	Sabbagh A	Human mutation	2013	PMID: 23913538
Germline NF1 mutational spectra and loss-of-heterozygosity analyses in patients with pheochromocytoma and neurofibromatosis type 1.	Bausch B	The Journal of clinical endocrinology and metabolism	2007	PMID: 17426081
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
NF1 mutations in neurofibromatosis 1 patients with plexiform neurofibromas.	Kluwe L	Human mutation	2002	PMID: 11857752
Evaluation of denaturing high performance liquid chromatography (DHPLC) for the mutational analysis of the neurofibromatosis type 1 ( NF1) gene.	Han SS	Human genetics	2001	PMID: 11735023
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
Mutations affecting mRNA splicing are the most common molecular defects in patients with neurofibromatosis type 1.	Ars E	Human molecular genetics	2000	PMID: 10607834

Text-mined citations for rs1060500355 ...

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.6921+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1060500355 ...