ClinVar Genomic variation as it relates to human health
NM_001042492.3(NF1):c.1318C>T (p.Arg440Ter)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001042492.3(NF1):c.1318C>T (p.Arg440Ter)
Variation ID: 230673 Accession: VCV000230673.46
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q11.2 17: 31206297 (GRCh38) [ NCBI UCSC ] 17: 29533315 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 May 29, 2016 Apr 15, 2024 Apr 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001042492.3:c.1318C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001035957.1:p.Arg440Ter nonsense NM_000267.3:c.1318C>T NP_000258.1:p.Arg440Ter nonsense NM_001128147.3:c.1318C>T NP_001121619.1:p.Arg440Ter nonsense NC_000017.11:g.31206297C>T NC_000017.10:g.29533315C>T NG_009018.1:g.116321C>T LRG_214:g.116321C>T LRG_214t1:c.1318C>T LRG_214p1:p.Arg440Ter LRG_214t2:c.1318C>T LRG_214p2:p.Arg440Ter - Protein change
- R440*
- Other names
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- Canonical SPDI
- NC_000017.11:31206296:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
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 | ||
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HI score
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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. |
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NF1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
13936 | 14346 |
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. |
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Pathogenic (1) |
criteria provided, single submitter
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Mar 4, 2015 | RCV000213237.2 | |
Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
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Apr 4, 2024 | RCV000225855.19 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Feb 16, 2022 | RCV000519956.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 9, 2022 | RCV000762984.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2021 | RCV001814122.2 | |
Neurofibrmatosis type 1
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Pathogenic (1) |
criteria provided, single submitter
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Oct 7, 2021 | RCV003315237.2 |
Pathogenic (1) |
criteria provided, single submitter
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Aug 6, 2023 | RCV003469010.1 |
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. |
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Pathogenic
(Nov 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781902.1
First in ClinVar: Jul 07, 2018 Last updated: Jul 07, 2018 |
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Pathogenic
(Dec 20, 2019)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
Affected status: yes
Allele origin:
germline
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Medical Genetics, University of Parma
Accession: SCV001218914.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
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Pathogenic
(Mar 04, 2015)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000274305.5
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
​<span style="background-color:initial">The p.R440* pathogenic mutation (also known as c.1318C>T), located in coding exon 12 of the NF1 gene, results from a C to T substitution … (more)
​<span style="background-color:initial">The p.R440* pathogenic mutation (also known as c.1318C>T), located in coding exon 12 of the NF1 gene, results from a C to T substitution at nucleotide position 1318. This changes the amino acid from an arginine to a stop codon within exon 12. This mutation has been reported in several individuals diagnosed with NF1 (Heim et al. Hum Mol Genet. 1995. 4(6):975-981; Fahsold et al. Am J Hum Genet. 2000. 66:790-818; Kluwe, et al. Hum Mutat. 2003 Nov;22(5):420). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, p.R440* is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med 2008;10:294). (less)
Number of individuals with the variant: 1
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Pathogenic
(Oct 26, 2020)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV001479031.1
First in ClinVar: Feb 13, 2021 Last updated: Feb 13, 2021 |
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Pathogenic
(Jul 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Abnormality of the skin
Affected status: yes
Allele origin:
de novo
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Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755241.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
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Pathogenic
(Feb 09, 2021)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
Affected status: yes
Allele origin:
maternal
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Baylor Genetics
Study: CSER-TexasKidsCanSeq
Accession: SCV002030196.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Jul 14, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV002771575.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with … (more)
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. (less)
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Pathogenic
(Jul 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV004014626.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Clinical Features:
Cafe-au-lait spot (present) , Subcutaneous neurofibroma (present)
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Pathogenic
(Oct 07, 2021)
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criteria provided, single submitter
Method: research
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Neurofibrmatosis type 1
Affected status: yes
Allele origin:
de novo
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Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital
Accession: SCV004012922.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
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Pathogenic
(Aug 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Juvenile myelomonocytic leukemia
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004198376.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Mar 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002561656.1
First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022 |
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Pathogenic
(Mar 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
Neurofibromatosis, familial spinal Café-au-lait macules with pulmonary stenosis Neurofibromatosis-Noonan syndrome Juvenile myelomonocytic leukemia
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893429.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Feb 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000616807.6
First in ClinVar: Dec 19, 2017 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 7655472, 11940628, 16835897, 31212687, 31717729, 25525159, 10712197, 26744134, 28454108, 9452037, 15060124, 10862084, 30014477, 10336779, 23668869, 14517963, 24232412, 25925892, 10543400, 30713041, 30290804, 31370276, 30530636, 31730495, 31776437, 29625052) (less)
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Pathogenic
(Apr 10, 2020)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
maternal
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Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center
Accession: SCV004037360.1
First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023 |
Comment:
The c. 1318C>T variant is a heterozygous single base pair substitution at nucleotide 1318 in exon 12 of 58 of the NF1 gene, resulting in … (more)
The c. 1318C>T variant is a heterozygous single base pair substitution at nucleotide 1318 in exon 12 of 58 of the NF1 gene, resulting in a premature translational stop signal at amino acid 440 of 2840 (p.Arg440Ter), and is expected to cause nonsense mediated mRNA decay. This variant is observed in the Genome Aggregation Database (gnomAD) at a very low frequency (2/251,412), indicating it is not a common benign variant in the populations represented in this database. This variant has been observed in the heterozygous state in multiple individuals with clinical features of Neurofibromatosis, type 1 (PMIDs: 24232412, 30530636, 7655472, 23668869, 16835897, 10862084, 10543400, 10712197, and 24922668). This variant has been reported in ClinVar as Pathogenic by multiple submitters (Variation ID: 230673; Last accessed: 3/25/2020). (less)
Clinical Features:
Cafe au lait spots, multiple (present) , Attention deficit hyperactivity disorder (present) , Global developmental delay (present)
Family history: yes
Age: 10-19 years
Sex: male
Ethnicity/Population group: Ashkenazi Jew
Tissue: DNA
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Pathogenic
(Jul 14, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004222152.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
This variant causes the premature termination of NF1 protein synthesis. In addition, this variant has been reported as pathogenic in individuals with Neurofibromatosis type 1 … (more)
This variant causes the premature termination of NF1 protein synthesis. In addition, this variant has been reported as pathogenic in individuals with Neurofibromatosis type 1 in the published literature (PMIDs: 7655472 (1995), 15060124 (2004), and 23668869 (2013)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Dec 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000284377.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg440*) in the NF1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg440*) 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). This variant is present in population databases (rs778405030, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with neurofibromatosis type 1 (PMID: 7655472, 10543400, 10712197, 10862084, 16835897, 23668869, 24922668). ClinVar contains an entry for this variant (Variation ID: 230673). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004809487.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001973749.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001954158.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Congenital Craniofacial Plexiform Neurofibroma in Neurofibromatosis Type 1. | Cacchione A | Diagnostics (Basel, Switzerland) | 2021 | PMID: 33540839 |
Risk of Optic Pathway Glioma in Neurofibromatosis Type 1: No Evidence of Genotype-Phenotype Correlations in A Large Independent Cohort. | Melloni G | Cancers | 2019 | PMID: 31766501 |
Clinical and Genetic Findings in Children with Neurofibromatosis Type 1, Legius Syndrome, and Other Related Neurocutaneous Disorders. | Giugliano T | Genes | 2019 | PMID: 31370276 |
SDHC epi-mutation testing in gastrointestinal stromal tumours and related tumours in clinical practice. | Casey RT | Scientific reports | 2019 | PMID: 31308404 |
Breast cancer risk in neurofibromatosis type 1 is a function of the type of NF1 gene mutation: a new genotype-phenotype correlation. | Frayling IM | Journal of medical genetics | 2019 | PMID: 30530636 |
Genetic diagnosis of neurofibromatosis type 1: targeted next- generation sequencing with Multiple Ligation-Dependent Probe Amplification analysis. | Wu-Chou YH | Journal of biomedical science | 2018 | PMID: 30290804 |
Molecular Characterization of NF1 and Neurofibromatosis Type 1 Genotype-Phenotype Correlations in a Chinese Population. | Zhang J | Scientific reports | 2015 | PMID: 26056819 |
Whole Exome Sequencing Reveals the Order of Genetic Changes during Malignant Transformation and Metastasis in a Single Patient with NF1-plexiform Neurofibroma. | Hirbe AC | Clinical cancer research : an official journal of the American Association for Cancer Research | 2015 | PMID: 25925892 |
NF1 truncating mutations associated to aggressive clinical phenotype with elephantiasis neuromatosa and solid malignancies. | Ponti G | Anticancer research | 2014 | PMID: 24922668 |
Jaffe-Campanacci syndrome, revisited: detailed clinical and molecular analyses determine whether patients have neurofibromatosis type 1, coincidental manifestations, or a distinct disorder. | Stewart DR | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24232412 |
NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience. | Sabbagh A | Human mutation | 2013 | PMID: 23913538 |
Mutation spectrum of NF1 and clinical characteristics in 78 Korean patients with neurofibromatosis type 1. | Ko JM | Pediatric neurology | 2013 | PMID: 23668869 |
Role of noncoding RNA ANRIL in genesis of plexiform neurofibromas in neurofibromatosis type 1. | Pasmant E | Journal of the National Cancer Institute | 2011 | PMID: 22034633 |
Identification of forty-five novel and twenty-three known NF1 mutations in Chinese patients with neurofibromatosis type 1. | Lee MJ | Human mutation | 2006 | PMID: 16835897 |
Genetic and phenotypic characterization of tumor cells derived from malignant peripheral nerve sheath tumors of neurofibromatosis type 1 patients. | Frahm S | Neurobiology of disease | 2004 | PMID: 15207265 |
Automated comparative sequence analysis identifies mutations in 89% of NF1 patients and confirms a mutation cluster in exons 11-17 distinct from the GAP related domain. | Mattocks C | Journal of medical genetics | 2004 | PMID: 15060124 |
Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. | Messiaen LM | Human mutation | 2000 | PMID: 10862084 |
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 |
Evaluation of the protein truncation test and mutation detection in the NF1 gene: mutational analysis of 15 known and 40 unknown mutations. | Osborn MJ | Human genetics | 1999 | PMID: 10543400 |
Analysis of CpG C-to-T mutations in neurofibromatosis type 1. Mutations in brief no. 129. Online. | Krkljus S | Human mutation | 1998 | PMID: 10336779 |
Homonucleotide tracts, short repeats and CpG/CpNpG motifs are frequent sites for heterogeneous mutations in the neurofibromatosis type 1 (NF1) tumour-suppressor gene. | Rodenhiser DI | Mutation research | 1997 | PMID: 9042399 |
Distribution of 13 truncating mutations in the neurofibromatosis 1 gene. | Heim RA | Human molecular genetics | 1995 | PMID: 7655472 |
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Text-mined citations for rs778405030 ...
HelpRecord last updated May 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.