ClinVar Genomic variation as it relates to human health
NM_001042492.3(NF1):c.3457_3460del (p.Leu1153fs)
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.3457_3460del (p.Leu1153fs)
Variation ID: 185963 Accession: VCV000185963.49
- Type and length
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Deletion, 4 bp
- Location
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Cytogenetic: 17q11.2 17: 31232841-31232844 (GRCh38) [ NCBI UCSC ] 17: 29559859-29559862 (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 Mar 24, 2015 Oct 20, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001042492.3:c.3457_3460del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001035957.1:p.Leu1153fs frameshift NM_000267.3:c.3456_3459delACTC frameshift NM_000267.3:c.3457_3460del NP_000258.1:p.Leu1153fs frameshift NM_000267.3:c.3457_3460delCTCA NM_001042492.2:c.3457_3460delCTCA NC_000017.11:g.31232842_31232845del NC_000017.10:g.29559860_29559863del NG_009018.1:g.142866_142869del LRG_214:g.142866_142869del LRG_214t1:c.3457_3460del LRG_214p1:p.Leu1153fs - Protein change
- Other names
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- Canonical SPDI
- NC_000017.11:31232840:ACTCA:A
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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
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The frequency of the allele represented by this VCV record.
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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
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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 |
14097 | 14534 |
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
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Jan 3, 2022 | RCV000165479.4 | |
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Jan 22, 2024 | RCV000168453.16 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Aug 5, 2022 | RCV000712406.31 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 13, 2021 | RCV001800492.2 | |
NF1-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Feb 28, 2024 | RCV004552910.3 |
Pathogenic (1) |
criteria provided, single submitter
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Dec 2, 2022 | RCV003468744.1 |
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: SCV000781986.1
First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017 |
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Pathogenic
(Apr 25, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics
Accession: SCV000842889.1
First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018 |
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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: SCV001479131.1
First in ClinVar: Feb 13, 2021 Last updated: Feb 13, 2021 |
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Pathogenic
(Dec 02, 2022)
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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: SCV004190775.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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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: SCV000588761.2
First in ClinVar: Aug 13, 2017 Last updated: Apr 18, 2020 |
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446556.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Neurofibroma (present)
Sex: female
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Pathogenic
(Aug 20, 2014)
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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: SCV000216210.4
First in ClinVar: Mar 24, 2015 Last updated: Mar 24, 2015 |
Comment:
The c.3457_3460delCTCA pathogenic mutation, located in coding exon 26 of the NF1 gene, results from a deletion of 4 nucleotides between nucleotide positions 3457 and … (more)
The c.3457_3460delCTCA pathogenic mutation, located in coding exon 26 of the NF1 gene, results from a deletion of 4 nucleotides between nucleotide positions 3457 and 3460, causing a translational frameshift with a predicted alternate stop codon.<span style="background-color: initial;">This alteration has been reported in multiple unrelated patients with a clinical diagnosis of NF1, including an individual with NF1 and a malignant peripheral nerve sheath tumor diagnosed at age 25 (<span style="background-color: initial;">Pros E, Hum. Mutat. 2008 Sep; 29(9):E173-93. Kluwe L, Hum. Mutat. 2003 Nov; 22(5):420. Ponti G, Hered Cancer Clin Pract<span style="background-color: initial;">2011; 9:6)<span style="background-color: initial;">. In addition to the clinical data presented in the literature, s<span style="background-color: initial;">ince frameshifts are typically deleterious in nature, this alteration 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
(Aug 05, 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: SCV001168586.5
First in ClinVar: Mar 16, 2020 Last updated: Mar 04, 2023 |
Comment:
Frameshift 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; Not … (more)
Frameshift 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; Not observed in large population cohorts (gnomAD); Also known as 3456delACTC; This variant is associated with the following publications: (PMID: 23668869, 29483232, 18546366, 9003501, 14517963, 29849115, 25541118, 21838856, 24922668, 29146900, 30098238, 31776437, 31717729, 33726816, 33674644, 34427956) (less)
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Pathogenic
(Apr 25, 2018)
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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: SCV004222165.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
This frameshift variant alters the translational reading frame of the NF1 mRNA and causes the premature termination of NF1 protein synthesis. This variant has not … (more)
This frameshift variant alters the translational reading frame of the NF1 mRNA and causes the premature termination of NF1 protein synthesis. This variant 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 neurofibromatosis 1 (PMID: 9003501 (1997), 18546366 (2008), 21838856 (2011), 31776437 (2020), 34427956 (2022)) and breast cancer (PMID: 33471991 (2021)). The variant has also been reported in a pediatric case of soft tissue sarcoma (PMID: 33674644 (2021)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Feb 02, 2022)
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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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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557495.2
First in ClinVar: Aug 08, 2022 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurofibromatosis type 1 (NF1; MIM#162200). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. A child can be more severely affected than the carrier parent (GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported multiple times as pathogenic in ClinVar and it has been identified in individuals with NF1 (PMID: 31776437). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Feb 03, 2021)
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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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Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University
Accession: SCV001571440.1
First in ClinVar: Apr 22, 2021 Last updated: Apr 22, 2021 |
Number of individuals with the variant: 1
Ethnicity/Population group: Japanese
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Pathogenic
(Dec 13, 2021)
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criteria provided, single submitter
Method: clinical testing
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Increased nuchal translucency
Cervical lymphadenopathy Abnormal lymph node morphology
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University Hospital Muenster
Accession: SCV002047379.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
Comment:
ACMG categories: PVS1,PM1,PM2,PP5
Number of individuals with the variant: 1
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002527511.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The NF1 c.3457_3460delCTCA (p.L1153MfsX4) variant has been reported in heterozygosity in at least 4 individuals with neurofibromatosis type 1 (PMID: 29849115, 31776437). It has been … (more)
The NF1 c.3457_3460delCTCA (p.L1153MfsX4) variant has been reported in heterozygosity in at least 4 individuals with neurofibromatosis type 1 (PMID: 29849115, 31776437). It has been reported in one individual with rhabdosarcoma and one individual with myelodysplastic syndrome (PMID: 33674644, 29146900). It has been also reported in a large breast cancer case-control study in 1/60466 cases and 0/53461 controls (PMID: 33471991). The variant causes a frameshift that results in premature termination 4 amino acids downstream. At this location, this variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This variant is not reported in the population database Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 185963). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
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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: SCV002559962.1
First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022 |
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Pathogenic
(Jan 22, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000219150.7
First in ClinVar: Mar 29, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Leu1153Metfs*4) 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.Leu1153Metfs*4) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with neurofibromatosis, type 1 (PMID: 9003501, 14517963, 18546366, 21838856, 25541118, 26969325). ClinVar contains an entry for this variant (Variation ID: 185963). 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)
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Pathogenic
(Jul 01, 2021)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001961672.20
First in ClinVar: Oct 08, 2021 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Feb 28, 2024)
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no assertion criteria provided
Method: clinical testing
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NF1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004749899.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The NF1 c.3457_3460delCTCA variant is predicted to result in a frameshift and premature protein termination (p.Leu1153Metfs*4). This variant has previously been reported in individuals with … (more)
The NF1 c.3457_3460delCTCA variant is predicted to result in a frameshift and premature protein termination (p.Leu1153Metfs*4). This variant has previously been reported in individuals with neurofibromatosis type 1 (referred to as 3456delACTC, Upadhyaya et al. 1997. PubMed ID: 9003501; Table 4, Noë et al. 2018. PubMed ID: 29849115; Warejko et al. 2018. PubMed ID: 29483232; Yao et al. 2019. PubMed ID: 31717729). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/185963/). Frameshift variants in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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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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Recurrent NF1 gene variants and their genotype/phenotype correlations in patients with Neurofibromatosis type I. | Riva M | Genes, chromosomes & cancer | 2022 | PMID: 34427956 |
Prevalence of germline pathogenic variants in 22 cancer susceptibility genes in Swedish pediatric cancer patients. | von Stedingk K | Scientific reports | 2021 | PMID: 33674644 |
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Phenotype categorization of neurofibromatosis type I and correlation to NF1 mutation types. | Kang E | Journal of human genetics | 2020 | PMID: 31776437 |
Clinical Presentation and Novel Pathogenic Variants among 68 Chinese Neurofibromatosis 1 Children. | Yao R | Genes | 2019 | PMID: 31717729 |
Whole-exome sequencing of duodenal neuroendocrine tumors in patients with neurofibromatosis type 1. | Noë M | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2018 | PMID: 29849115 |
Whole Exome Sequencing Reveals a Monogenic Cause of Disease in ≈43% of 35 Families With Midaortic Syndrome. | Warejko JK | Hypertension (Dallas, Tex. : 1979) | 2018 | PMID: 29483232 |
The genomic landscape of pediatric myelodysplastic syndromes. | Schwartz JR | Nature communications | 2017 | PMID: 29146900 |
No correlation between NF1 mutation position and risk of optic pathway glioma in 77 unrelated NF1 patients. | Hutter S | Human genetics | 2016 | PMID: 26969325 |
[Phenotypic and genetic features in neurofibromatosis type 1 in children]. | Duat Rodríguez A | Anales de pediatria (Barcelona, Spain : 2003) | 2015 | PMID: 25541118 |
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 |
Clinico-pathological and biomolecular findings in Italian patients with multiple cutaneous neurofibromas. | Ponti G | Hereditary cancer in clinical practice | 2011 | PMID: 21838856 |
Nature and mRNA effect of 282 different NF1 point mutations: focus on splicing alterations. | Pros E | Human mutation | 2008 | PMID: 18546366 |
Constitutional NF1 mutations in neurofibromatosis 1 patients with malignant peripheral nerve sheath tumors. | Kluwe L | Human mutation | 2003 | PMID: 14517963 |
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 |
Mutational and functional analysis of the neurofibromatosis type 1 (NF1) gene. | Upadhyaya M | Human genetics | 1997 | PMID: 9003501 |
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Text-mined citations for rs1321848637 ...
HelpRecord last updated Oct 27, 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.