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 (Lek 2016); This variant is associated with the following publications: (PMID: 12807981, 18546366, 10712197, 23913538)
ClinVar Genomic variation as it relates to human health
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- Interpretation:
-
Pathogenic
- Review status:
- criteria provided, multiple submitters, no conflicts
- Submissions:
- 8
- First in ClinVar:
- Apr 27, 2017
- Most recent Submission:
- Feb 13, 2023
- Last evaluated:
- May 24, 2022
- Accession:
- VCV000420078.50
- Variation ID:
- 420078
- Description:
- 4bp deletion
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NM_001042492.3(NF1):c.3739_3742del (p.Phe1247fs)
- Allele ID
- 409871
- Variant type
- Deletion
- Variant length
- 4 bp
- Cytogenetic location
- 17q11.2
- Genomic location
- 17: 31235639-31235642 (GRCh38) GRCh38 UCSC
- 17: 29562657-29562660 (GRCh37) GRCh37 UCSC
- HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001042492.3:c.3739_3742del MANE Select NP_001035957.1:p.Phe1247fs frameshift NM_000267.3:c.3739_3742del NP_000258.1:p.Phe1247fs frameshift NM_000267.3:c.3739_3742delTTTG NM_001042492.2:c.3739_3742delTTTG NC_000017.11:g.31235641_31235644del NC_000017.10:g.29562659_29562662del NG_009018.1:g.145665_145668del LRG_214:g.145665_145668del LRG_214t1:c.3739_3742del LRG_214p1:p.Phe1247fs - Protein change
- F1247fs
- Other names
- -
- Canonical SPDI
- NC_000017.11:31235638:TGTTTG:TG
- Functional consequence
- -
- Global minor allele frequency (GMAF)
- -
- Allele frequency
- -
- Links
- ClinGen: CA16620366
- dbSNP: rs1064794276
- VarSome
Help
Aggregate interpretations per condition
| Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
|---|---|---|---|---|---|
| Pathogenic | 5 | criteria provided, multiple submitters, no conflicts | May 24, 2022 | RCV000696868.11 | |
| Pathogenic | 1 | criteria provided, single submitter | Jul 17, 2020 | RCV000482277.2 | |
| Pathogenic | 1 | criteria provided, single submitter | Jun 6, 2014 | RCV000492776.3 | |
| Pathogenic | 1 | criteria provided, single submitter | Jun 3, 2019 | RCV002319010.1 |
Clinical features observed in individuals with this variant
Submitted interpretations and evidence
Help| Interpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | More information | |
|---|---|---|---|---|---|
|
Pathogenic
(May 22, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Neurofibromatosis, type 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital
Accession: SCV000914230.1
First in ClinVar: May 24, 2019 Last updated: May 24, 2019 |
Zygosity: 1 Single Heterozygote
|
|
|
Pathogenic
(Oct 26, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Neurofibromatosis, type 1
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV001479030.1
First in ClinVar: Feb 13, 2021 Last updated: Feb 13, 2021 |
|
|
|
Pathogenic
(Jul 17, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000568605.5
First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017 |
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 (Lek 2016); This variant is associated with the following publications: (PMID: 12807981, 18546366, 10712197, 23913538) (less)
|
|
|
Pathogenic
(Mar 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Neurofibromatosis, type 1
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002559985.1
First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022 |
|
|
|
Pathogenic
(May 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Neurofibromatosis, type 1
Affected status: yes
Allele origin:
de novo
|
Institute of Medical Genetics, University of Zurich
Accession: SCV002569059.1
First in ClinVar: Feb 13, 2023 Last updated: Feb 13, 2023 |
|
|
|
Pathogenic
(Jun 03, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001182568.3
First in ClinVar: Mar 16, 2020 Last updated: Nov 29, 2022 |
Comment:
The c.3739_3742delTTTG pathogenic mutation, located in coding exon 28 of the NF1 gene, results from a deletion of 4 nucleotides between nucleotide positions 3739 and … (more)
The c.3739_3742delTTTG pathogenic mutation, located in coding exon 28 of the NF1 gene, results from a deletion of 4 nucleotides between nucleotide positions 3739 and 3742, causing a translational frameshift with a predicted alternate stop codon (p.F1247Ifs*18). This mutation has been reported in two individuals with features suggestive of neurofibromatosis type 1 (NF1), at least one of whom met clinical diagnostic criteria for NF1 (Fahsold R et al. Am. J. Hum. Genet. 2000 Mar; 66(3):790-818. Ars E et al. J. Med. Genet. 2003 Jun; 40(6):e82). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jun 06, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000581245.5
First in ClinVar: Jul 01, 2017 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Pes planus (present) , Hyperkeratosis (present) , Hemangioma (present) , Abnormality of the ankles (present) , Multiple cafe-au-lait spots (present) , Relative macrocephaly (present) , … (more)
Pes planus (present) , Hyperkeratosis (present) , Hemangioma (present) , Abnormality of the ankles (present) , Multiple cafe-au-lait spots (present) , Relative macrocephaly (present) , Malar flattening (present) , Downslanted palpebral fissures (present) , Protruding ear (present) , Short stature (present) , Axillary freckling (present) , Inguinal freckling (present) (less)
Sex: male
Ethnicity/Population group: Caucasian
|
|
|
Pathogenic
(Dec 29, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Neurofibromatosis, type 1
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000825448.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 07, 2023 |
Comment:
This sequence change creates a premature translational stop signal (p.Phe1247Ilefs*18) 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.Phe1247Ilefs*18) 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 individual(s) with neurofibromatosis type I (PMID: 10712197, 18546366). ClinVar contains an entry for this variant (Variation ID: 420078). For these reasons, this variant has been classified as Pathogenic. (less)
|
Functional evidence
Help| 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 this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. | Nykamp K | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28492532 |
| NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience. | Sabbagh A | Human mutation | 2013 | PMID: 23913538 |
| Nature and mRNA effect of 282 different NF1 point mutations: focus on splicing alterations. | Pros E | Human mutation | 2008 | PMID: 18546366 |
| Recurrent mutations in the NF1 gene are common among neurofibromatosis type 1 patients. | Ars E | Journal of medical genetics | 2003 | PMID: 12807981 |
| 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 rs1064794276...
HelpThese 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 Jun 04, 2023