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.
ClinVar Genomic variation as it relates to human health
NM_001042492.3(NF1):c.3739_3742del (p.Phe1247fs)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic
12 out of 12 submissions contributed to this classification
Help
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.
12
Somatic
Clinical impact
Help
criteria provided, single submitter. Learn more about how ClinVar calculates review status.
This classification is based on the single submission received
Help
The aggregate somatic clinical impact for this variant for one or more tumor types, using the AMP/ASCO/CAP terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
1
Somatic
Oncogenicity
Help
criteria provided, single submitter. Learn more about how ClinVar calculates review status.
Likely oncogenic
This classification is based on the single submission received
Help
The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
1
Variant Details
- Identifiers
-
NM_001042492.3(NF1):c.3739_3742del (p.Phe1247fs)
Variation ID: 420078 Accession: VCV000420078.84
- Type and length
-
Deletion, 4 bp
- Location
-
Cytogenetic: 17q11.2 17: 31235639-31235642 (GRCh38) [ NCBI UCSC ] 17: 29562657-29562660 (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 Apr 27, 2017 Jul 13, 2025 Apr 28, 2025 Somatic - Clinical impact Nov 22, 2025 Nov 22, 2025 Apr 2, 2025 Somatic - Oncogenicity Aug 11, 2024 Mar 11, 2025 Mar 4, 2025 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001042492.3:c.3739_3742del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001035957.1:p.Phe1247fs frameshift NM_000267.3:c.3739_3742delTTTG frameshift NM_000267.4:c.3739_3742delTTTG NP_000258.1:p.Phe1247Ilefs frameshift 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 LRG_214t2:c.3739_3742del LRG_214p2:p.Phe1247Ilefs - Protein change
- F1247fs
- Other names
-
p.Phe1247Ilefs*18
- Canonical SPDI
- NC_000017.11:31235638:TGTTTG:TG
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
16242 | 16798 | |
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. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 28, 2025 | RCV000482277.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 6, 2014 | RCV000492776.11 | |
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Nov 2, 2024 | RCV000696868.25 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 3, 2019 | RCV002319010.8 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 22, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neurofibromatosis, type 1
(Autosomal dominant inheritance)
|
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000914230.1
First in ClinVar: May 24, 2019 Last updated: May 24, 2019 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Zygosity: Single Heterozygote
|
|
|
Pathogenic
(Oct 26, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neurofibromatosis, type 1 |
Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV001479030.1
First in ClinVar: Feb 13, 2021 Last updated: Feb 13, 2021 |
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
(Mar 15, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neurofibromatosis, type 1 |
Genome-Nilou Lab
Accession: SCV002559985.1
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
(May 24, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neurofibromatosis, type 1 |
Institute of Medical Genetics, University of Zurich
Accession: SCV002569059.2
First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: de novo
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: de novo
Affected status: yes
|
|
|
Pathogenic
(Jun 03, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiovascular phenotype
Hereditary cancer-predisposing syndrome |
Ambry Genetics
Accession: SCV001182568.3
First in ClinVar: Mar 16, 2020 Last updated: Nov 29, 2022 |
Comment:
show
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)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 1
|
|
|
Pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neurofibromatosis, type 1
(Autosomal dominant inheritance)
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005042882.1
First in ClinVar: May 12, 2024 Last updated: May 12, 2024 |
Comment:
show
The frameshift c.3739_3742delp.Phe1247IlefsTer18 variant in NF1 gene has been reported in heterozygous state in multiple individuals affected with neurofibromatosis type 1 Tang J, et. al., 2022; Pemov, A., et al., 2010; Ars E, et. al., 2003. The p.Phe1247IlefsTer18 variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic multiple submissions. This variant causes a frameshift starting with codon Phenylalanine 1247, changes this amino acid to Isoleucine residue, and creates a premature Stop codon at position 18 of the new reading frame, denoted p.Phe1247IlefsTer18. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Clinical Features:
Upper motor neuron dysfunction (present)
|
|
|
Pathogenic
(Jul 30, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Not provided |
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005413202.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 36
|
|
|
Pathogenic
(Nov 02, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neurofibromatosis, type 1 |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000825448.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 25, 2025 |
Comment:
show
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)
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
(Jun 06, 2014)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Inborn genetic diseases |
Ambry Genetics
Accession: SCV000581245.6
First in ClinVar: Jul 01, 2017 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
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) , Malar flattening (present) , Downslanted palpebral fissures (present) , Protruding ear (present) , Short stature (present) , Axillary freckling (present) , Inguinal freckling (present)
Sex: male
Ethnicity/Population group: Caucasian
|
|
|
Pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neurofibromatosis, type 1 |
Sun Health (Beijing), Ltd.
Accession: SCV005911638.1
First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025 |
Comment:
show
Neurofibromatosis Type 1 (NF1) is an autosomal dominant disorder caused by mutations in the NF1 gene located at chromosome 17q11.2. This condition is characterized by highly recognizable clinical features, including cutaneous café-au-lait macules, multiple neurofibromas, Lisch nodules of the iris, and optic pathway gliomas, with potential multisystem involvement affecting the skin, nervous system, bones, gastrointestinal tract, and cardiovascular system. In this case, a heterozygous variant in the NF1 gene (c.3739_3742del, p.Phe1247Ilefs*18) was identified, representing a frameshift mutation. This variant involves a deletion of nucleotides at positions 3739–3742 in the NF1 gene, resulting in the substitution of phenylalanine at position 1247 with isoleucine and the introduction of a premature stop codon 18 amino acids downstream. This leads to truncated protein synthesis, affecting protein structure and function. The variant is located in exon 28, within the GRD functional region, which strongly supports its pathogenic potential. According to the ACMG variant classification guidelines, this variant is classified as "pathogenic." Although Sanger sequencing of parental peripheral blood did not detect the c.3739_3742del variant, the possibility of low-level mosaicism in either parent cannot be entirely excluded, indicating that this is a de novo mutation in the proband. (less)
Observation 1
Collection method: clinical testing
Allele origin: de novo
Affected status: yes
Age: 10-19 years
Comment on evidence:
A 12-year-and-7-month-old boy presented with a history of "slow growth since early childhood." He was the first live birth of his mother's fourth pregnancy, delivered … (more)
A 12-year-and-7-month-old boy presented with a history of "slow growth since early childhood." He was the first live birth of his mother's fourth pregnancy, delivered vaginally at a gestational age of 37+5 weeks, with no history of birth trauma or neonatal asphyxia. His birth weight was 2.8 kg, and birth length was not recorded. Compared to peers of the same age and sex, his height had consistently been below average, although specific annual growth velocity is unclear. He frequently experiences fatigue after routine physical activities and had relatively low activity levels. Deformity with restricted mobility was noted in the left wrist and forearm. Language and gross motor development were normal. There was no family history of skeletal deformities in either parent or among the grandparents. The mother had a history of five pregnancies and two live births, with the first three pregnancies ended in early miscarriages (gestational age <6 months). The fifth pregnancy resulted in the birth of a healthy girl, now 10 years old. The proband had no significant past medical history or history of traumatic fractures. Both parents denied any family history of similar or other cutaneous manifestations. Pubertal development in both parents was normal. The father's height is 164.7 cm, and the mother's height is 147.6 cm, yielding a mid-parental target height of 162.6 cm for the proband. (less)
Method: Laboratory tests revealed the following results: alanine aminotransferase (ALT) 15.9 U/L, aspartate aminotransferase (AST) 26.3 U/L, urea 4.7 mmol/L, creatinine 45.7 μmol/L, serum phosphorus 1.37 mmol/L, serum magnesium 0.88 mmol/L, serum calcium 2.52 mmol/L, and alkaline phosphatase (ALP) 688 U/L. The calcium-phosphorus product was 25.9. Serum 25(OH)D level was 71.29 nmol/L (reference range: 75-200 nmol/L). Intact parathyroid hormone (iPTH) was 45.7 ng/L (reference range: 14.9-56.9 ng/L). Endogenous creatinine clearance, random urine calcium/creatinine ratio, and 24-hour urinary calcium excretion were not performed at our institution. Arterial blood gas analysis was within normal limits. Hormonal assays showed LH 1.16 mIU/mL, FSH 2.53 mIU/mL, E2 5.00 pg/mL, T 0.68 nmol/L, and hCG 1.16 mIU/mL. A growth hormone stimulation test demonstrated a peak GH level of 5.56 ng/mL. External laboratory tests included cortisol 17.07 µg/dL, adrenocorticotropic hormone (ACTH) 51.57 pg/mL, and 17α-hydroxyprogesterone (17α-OHP) 0.98 ng/mL. IGF-1 was 221.53 ng/mL, IGFBP-3 was 33.1 µg/mL, and inhibin B was 161.60 pg/mL. Chromosomal karyotype showed a normal male karyotype (46,XY).
|
|
|
Pathogenic
(Apr 28, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Not Provided |
GeneDx
Accession: SCV000568605.6
First in ClinVar: Apr 27, 2017 Last updated: May 03, 2025 |
Comment:
show
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 at significant frequency in large population cohorts (gnomAD); Also known as c.3737_3740delTGTT; This variant is associated with the following publications: (PMID: 18546366, 23913538, 12807981, 10712197, 36612057) (less)
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
(May 24, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neurofibromatosis, type 1
(Autosomal dominant inheritance)
|
Molecular Pathology, Peter Maccallum Cancer Centre
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV006276570.1
First in ClinVar: Jul 13, 2025 Last updated: Jul 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
Comment:
Comment:
The frameshift c.3739_3742delp.Phe1247IlefsTer18 variant in NF1 gene has been reported in heterozygous state in multiple individuals affected with neurofibromatosis type 1 Tang J, et. al., 2022; Pemov, A., et al., 2010; Ars E, et. al., 2003. The p.Phe1247IlefsTer18 variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic multiple submissions. This variant causes a frameshift starting with codon Phenylalanine 1247, changes this amino acid to Isoleucine residue, and creates a premature Stop codon at position 18 of the new reading frame, denoted p.Phe1247IlefsTer18. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
PP4, PM2, PS4_moderate, PVS1
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 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.
Comment:
Neurofibromatosis Type 1 (NF1) is an autosomal dominant disorder caused by mutations in the NF1 gene located at chromosome 17q11.2. This condition is characterized by highly recognizable clinical features, including cutaneous café-au-lait macules, multiple neurofibromas, Lisch nodules of the iris, and optic pathway gliomas, with potential multisystem involvement affecting the skin, nervous system, bones, gastrointestinal tract, and cardiovascular system. In this case, a heterozygous variant in the NF1 gene (c.3739_3742del, p.Phe1247Ilefs*18) was identified, representing a frameshift mutation. This variant involves a deletion of nucleotides at positions 3739–3742 in the NF1 gene, resulting in the substitution of phenylalanine at position 1247 with isoleucine and the introduction of a premature stop codon 18 amino acids downstream. This leads to truncated protein synthesis, affecting protein structure and function. The variant is located in exon 28, within the GRD functional region, which strongly supports its pathogenic potential. According to the ACMG variant classification guidelines, this variant is classified as "pathogenic." Although Sanger sequencing of parental peripheral blood did not detect the c.3739_3742del variant, the possibility of low-level mosaicism in either parent cannot be entirely excluded, indicating that this is a de novo mutation in the proband.
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 observed at significant frequency in large population cohorts (gnomAD); Also known as c.3737_3740delTGTT; This variant is associated with the following publications: (PMID: 18546366, 23913538, 12807981, 10712197, 36612057)
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in embryonal rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 34166060, 24436047, 26138366, 21412928).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A Translational Approach to Spinal Neurofibromatosis: Clinical and Molecular Insights from a Wide Italian Cohort. | Paterra R | Cancers | 2022 | PMID: 36612057 |
| 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 |
Conditions - Somatic
| Tumor type
Help
The tumor type for this variant-condition (RCV) record in ClinVar. |
Clinical impact (# of submissions)
Help
The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Oncogenicity
Help
The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
Variation/condition record
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
|---|---|---|---|---|
|
Likely oncogenic
criteria provided, single submitter
|
Mar 4, 2025 | RCV004668992.2 | ||
|
Tier I (Strong)
- diagnostic
- supports diagnosis
(1)
|
Apr 2, 2025 | RCV006254064.1 |
Submissions - Somatic
|
Clinical impact
Help
The submitted somatic clinical impact 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) |
Tumor type
Help
The tumor type 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
Help
This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|
|
Tier I (Strong)
- Diagnostic
-
supports diagnosis (Apr 02, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Embryonal rhabdomyosarcoma |
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV007104927.1
First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025 |
Comment:
show
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in embryonal rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 34166060, 24436047, 26138366, 21412928). (less)
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
|
Oncogenicity
Help
The submitted oncogenicity 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) |
Tumor type
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The tumor type 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
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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. |
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This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely oncogenic
(Mar 04, 2025)
C
Contributing to aggregate classification
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criteria provided, single submitter
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Neoplasm |
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005094483.2
First In ClinVar: Aug 11, 2024 Last updated: Mar 11, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
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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 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.
Comment:
The frameshift c.3739_3742delp.Phe1247IlefsTer18 variant in NF1 gene has been reported in heterozygous state in multiple individuals affected with neurofibromatosis type 1 Tang J, et. al., 2022; Pemov, A., et al., 2010; Ars E, et. al., 2003. The p.Phe1247IlefsTer18 variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic multiple submissions. This variant causes a frameshift starting with codon Phenylalanine 1247, changes this amino acid to Isoleucine residue, and creates a premature Stop codon at position 18 of the new reading frame, denoted p.Phe1247IlefsTer18. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
PP4, PM2, PS4_moderate, PVS1
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 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.
Comment:
Neurofibromatosis Type 1 (NF1) is an autosomal dominant disorder caused by mutations in the NF1 gene located at chromosome 17q11.2. This condition is characterized by highly recognizable clinical features, including cutaneous café-au-lait macules, multiple neurofibromas, Lisch nodules of the iris, and optic pathway gliomas, with potential multisystem involvement affecting the skin, nervous system, bones, gastrointestinal tract, and cardiovascular system. In this case, a heterozygous variant in the NF1 gene (c.3739_3742del, p.Phe1247Ilefs*18) was identified, representing a frameshift mutation. This variant involves a deletion of nucleotides at positions 3739–3742 in the NF1 gene, resulting in the substitution of phenylalanine at position 1247 with isoleucine and the introduction of a premature stop codon 18 amino acids downstream. This leads to truncated protein synthesis, affecting protein structure and function. The variant is located in exon 28, within the GRD functional region, which strongly supports its pathogenic potential. According to the ACMG variant classification guidelines, this variant is classified as "pathogenic." Although Sanger sequencing of parental peripheral blood did not detect the c.3739_3742del variant, the possibility of low-level mosaicism in either parent cannot be entirely excluded, indicating that this is a de novo mutation in the proband.
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 observed at significant frequency in large population cohorts (gnomAD); Also known as c.3737_3740delTGTT; This variant is associated with the following publications: (PMID: 18546366, 23913538, 12807981, 10712197, 36612057)
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in embryonal rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 34166060, 24436047, 26138366, 21412928).
Citations for somatic classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genomic Classification and Clinical Outcome in Rhabdomyosarcoma: A Report From an International Consortium. | Shern JF | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2021 | PMID: 34166060 |
| Characterization of Two Loss-of-Function NF1 Variants in Chinese Patients and Potential Molecular Interpretations of Phenotypes. | Zhang T | Frontiers in genetics | 2021 | PMID: 34046057 |
| Integrated genetic and epigenetic analysis defines novel molecular subgroups in rhabdomyosarcoma. | Seki M | Nature communications | 2015 | PMID: 26138366 |
| Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. | Shern JF | Cancer discovery | 2014 | PMID: 24436047 |
| High-resolution array CGH identifies common mechanisms that drive embryonal rhabdomyosarcoma pathogenesis. | Paulson V | Genes, chromosomes & cancer | 2011 | PMID: 21412928 |
| Recurrent mutations in the NF1 gene are common among neurofibromatosis type 1 patients. | Ars E | Journal of medical genetics | 2003 | PMID: 12807981 |
Text-mined citations for rs1064794276 ...
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Record last updated Dec 01, 2025
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.