VCV000547678.5 - ClinVar

NM_001042492.3(NF1):c.6669C>A (p.Cys2223Ter)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

5 out of 5 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001042492.3(NF1):c.6669C>A (p.Cys2223Ter)

Variation ID: 547678 Accession: VCV000547678.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q11.2 17: 29664863 (GRCh37) [ NCBI UCSC ] 17: 31337845 (GRCh38) [ 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 9, 2018	Jan 6, 2024	Mar 15, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001042492.3:c.6669C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001035957.1:p.Cys2223Ter	nonsense
NM_000267.4:c.6606C>A	NP_000258.1:p.Cys2202Ter	nonsense
NC_000017.11:g.31337845C>A
NC_000017.10:g.29664863C>A
NG_009018.1:g.247869C>A
LRG_214:g.247869C>A
LRG_214t1:c.6606C>A	LRG_214p1:p.Cys2202Ter
LRG_214t2:c.6669C>A	LRG_214p2:p.Cys2223Ter

... more HGVS ... less HGVS

Protein change

C2202*, C2223*

Other names

Canonical SPDI

NC_000017.11:31337844:C:A

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: CA399013798 dbSNP: rs1555534918 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	16702	17265

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/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 15, 2022	RCV000660097.4
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 11, 2021	RCV001662722.3

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.	Expand all rows Collapse all rows 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.
Likely pathogenic (Nov 01, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Neurofibromatosis, type 1	Center for Human Genetics, Inc, Center for Human Genetics, Inc Accession: SCV000782078.1 First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Jun 17, 2020) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Neurofibromatosis, type 1	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001581195.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021	Publications: PubMed (3) PubMed: 31370276‚ 23913538‚ 10712197 Comment: show This sequence change creates a premature translational stop signal (p.Cys2202*) in the NF1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 31370276, 23913538). ClinVar contains an entry for this variant (Variation ID: 547678). Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Mar 11, 2021) C Contributing to aggregate classification	criteria provided, single submitter (Athena Diagnostics criteria)	not provided	Athena Diagnostics Accession: SCV001879401.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Publications: PubMed (2) PubMed: 23913538‚ 31370276 Comment: show This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Mar 15, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Neurofibromatosis, type 1	Genome-Nilou Lab Accession: SCV002560197.1 First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Pathogenic (Mar 11, 2021) C Contributing to aggregate classification	criteria provided, single submitter (Quest Diagnostics criteria)	not provided	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004222177.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (2) PubMed: 23913538‚ 31370276 Comment: show The NF1 c.6606C>A (p.Cys2202*) nonsense variant causes the premature termination of NF1 protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with NF1 (PMID: 23913538 (2013)) or clinical features associated with NF1 (PMID: 31370276 (2019)). Based on the available information, this variant is classified as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Comment:

This sequence change creates a premature translational stop signal (p.Cys2202*) in the NF1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 31370276, 23913538). ClinVar contains an entry for this variant (Variation ID: 547678). Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). For these reasons, this variant has been classified as Pathogenic.

Comment:

This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene.

Comment:

The NF1 c.6606C>A (p.Cys2202*) nonsense variant causes the premature termination of NF1 protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with NF1 (PMID: 23913538 (2013)) or clinical features associated with NF1 (PMID: 31370276 (2019)). Based on the available information, this variant is classified as pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical and Genetic Findings in Children with Neurofibromatosis Type 1, Legius Syndrome, and Other Related Neurocutaneous Disorders.	Giugliano T	Genes	2019	PMID: 31370276
NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience.	Sabbagh A	Human mutation	2013	PMID: 23913538
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 rs1555534918 ...

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 Aug 09, 2025