ClinVar Genomic variation as it relates to human health
NM_001042492.3(NF1):c.5902C>T (p.Arg1968Ter)
Germline
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.
(20)
Help
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.
Pathogenic
20
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
Oncogenicity
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)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate oncogenicity 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.
Likely oncogenic
1
criteria provided, single submitter
Variant Details
- Identifiers
-
NM_001042492.3(NF1):c.5902C>T (p.Arg1968Ter)
Variation ID: 343 Accession: VCV000000343.42
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q11.2 17: 31334927 (GRCh38) [ NCBI UCSC ] 17: 29661945 (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 Aug 21, 2015 Oct 20, 2024 Mar 29, 2024 Somatic - Oncogenicity Aug 11, 2024 Aug 11, 2024 Jul 31, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001042492.3:c.5902C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001035957.1:p.Arg1968Ter nonsense NM_000267.3:c.5839C>T NP_000258.1:p.Arg1947Ter nonsense NC_000017.11:g.31334927C>T NC_000017.10:g.29661945C>T NG_009018.1:g.244951C>T LRG_214:g.244951C>T LRG_214t1:c.5839C>T LRG_214p1:p.Arg1947Ter LRG_214t2:c.5902C>T LRG_214p2:p.Arg1968Ter - Protein change
- R1947*, R1968*
- Other names
- -
- Canonical SPDI
- NC_000017.11:31334926:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- 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 |
14121 | 14559 | |
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 (9) |
criteria provided, multiple submitters, no conflicts
|
Mar 29, 2024 | RCV000000371.23 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
May 27, 2022 | RCV000418287.25 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 4, 2014 | RCV000492774.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 10, 2018 | RCV001009602.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000762995.3 | |
|
NF1-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Sep 28, 2022 | RCV004547450.1 |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 3, 2021 | RCV003460398.1 | |
| Pathogenic (1) |
no assertion criteria provided
|
Oct 23, 2023 | RCV004562178.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 14, 2021 | RCV004558221.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Dec 20, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Neurofibromatosis, type 1
Affected status: yes
Allele origin:
germline
|
Medical Genetics, University of Parma
Accession: SCV001218924.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 |
|
|
|
Pathogenic
(Mar 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Neurofibromatosis, type 1
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002560158.1
First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022 |
|
|
|
Pathogenic
(Dec 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Neurofibromatosis, type 1
Affected status: yes
Allele origin:
germline
|
Human Genetics Bochum, Ruhr University Bochum
Accession: SCV002758612.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
Comment:
ACMG criteria used to clasify this variant: PVS1, PM1, PM2, PS4
|
|
|
Pathogenic
(Aug 10, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Neurofibromatosis, type 1
Affected status: yes
Allele origin:
inherited
|
Center of Genomic medicine, Geneva, University Hospital of Geneva
Accession: SCV000693463.2
First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022 |
Age: 0-9 years
Sex: male
|
|
|
Pathogenic
(Jan 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000521066.7
First in ClinVar: Mar 08, 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; Not … (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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15146469, 16944272, 22913777, 8845843, 9042399, 25525159, 9195229, 24232412, 1757093, 18546366, 12552569, 27322474, 22155606, 7649559, 11015700, 10721668, 7903661, 8385067, 9101300, 2114220, 26969325, 10076878, 21354044, 29178821, 28124441, 19142971, 16117786, 30290804, 31533797, 31370276, 33443663) (less)
|
|
|
Pathogenic
(Sep 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
NF1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004120348.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The NF1 c.5902C>T variant is predicted to result in premature protein termination (p.Arg1968*). This variant, referred to as c.5839C>T (p.Arg1947*) in an alternate transcript (NM_000267.3), … (more)
The NF1 c.5902C>T variant is predicted to result in premature protein termination (p.Arg1968*). This variant, referred to as c.5839C>T (p.Arg1947*) in an alternate transcript (NM_000267.3), has been reported in multiple individuals with neurofibromatosis type 1 (see for example - Fashold et al. 2000. PubMed ID: 10712197; de Luca et al. 2004. PubMed ID: 15146469). To our knowledge, 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/343/). Nonsense variants in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(Jan 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Neurofibromatosis, type 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000260568.9
First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg1947*) 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.Arg1947*) 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 clinical features of neurofibromatosis type 1 (PMID: 2114220, 7649559, 7903661, 8069310, 8385067, 10076878; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as 1087C>T and c.5902C>T (Arg1968Ter). ClinVar contains an entry for this variant (Variation ID: 343). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Neurofibromatosis, type 1
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807877.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
|
|
Pathogenic
(Oct 14, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Hereditary cancer-predisposing syndrome
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV005048263.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
Comment:
The c.5839C>T (p.R1947*) alteration, located in exon 39 (coding exon 39) of the NF1 gene, consists of a C to T substitution at nucleotide position … (more)
The c.5839C>T (p.R1947*) alteration, located in exon 39 (coding exon 39) of the NF1 gene, consists of a C to T substitution at nucleotide position 5839. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 1947. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This pathogenic mutation (also known as p.R1968* (c.5902C>T) in the NM_001042492 isoform) has been described as a recurring mutation in individuals meeting diagnostic criteria for Neurofibromatosis type 1 (NF1) (Cawthon, 1990; Fahsold, 2000; Ars, 2003; Stewart, 2014; Hutter, 2016). In addition, it is located in a mutational hotspot of CpG dinucloetide repeats and methylated site of the gene (Andrews, 1996). Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
|
Pathogenic
(May 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002545911.16
First in ClinVar: Jul 09, 2022 Last updated: Oct 20, 2024 |
Comment:
NF1: PVS1, PM2
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Feb 07, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000842894.1
First in ClinVar: Sep 21, 2018 Last updated: Sep 21, 2018 |
|
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
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
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893440.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Nov 10, 2018)
|
criteria provided, single submitter
Method: research
|
Neurofibromatosis, type 1
Tibial pseudoarthrosis
Affected status: yes
Allele origin:
de novo
|
The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital
Accession: SCV001169703.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Multiple Cafe-au-lait spots (present) , Tibial pseudoarthrosis (present)
Age: 0-9 years
Sex: female
Ethnicity/Population group: Han Chinese
Geographic origin: China
Testing laboratory: Hunan Children’s Hospital
Date variant was reported to submitter: 2018-09-27
|
|
|
Pathogenic
(Nov 04, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000581242.3
First in ClinVar: Jul 01, 2017 Last updated: Jul 01, 2017 |
Comment:
The p.R1968* pathogenic mutation (also known as c.5902C>T) located in coding exon 40 of the NF1 gene, results from a C to T substitution at … (more)
The p.R1968* pathogenic mutation (also known as c.5902C>T) located in coding exon 40 of the NF1 gene, results from a C to T substitution at nucleotide position 5902. This changes the amino acid from an arginine to a stop codon within coding exon 40. This pathogenic mutation has been described as a recurring mutation in individuals with neurofibromatosis type 1 (Ars E et al. J. Med. Genet. 2003; 40:e82, Fahsold R et al. Am. J. Hum. Genet. 2000; 66:790-818). In addtition, it is located in a mutational hotspot of CpG dinucloetide repeats and methylated site of the gene (Andrews JD et al. Hum. Mol. Genet. 1996, 5:503-7). In addition to the clinical data presented in the literature, since premature stop codons 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). This pathogenic mutation is also known as p.R1947* (c.5839C>T) in the literature. (less)
Number of individuals with the variant: 1
|
|
|
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: SCV001479211.1
First in ClinVar: Feb 13, 2021 Last updated: Feb 13, 2021 |
|
|
|
Pathogenic
(Sep 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Juvenile myelomonocytic leukemia
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004199015.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Pathogenic
(May 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005196977.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Pathogenic
(Jan 01, 2000)
|
no assertion criteria provided
Method: literature only
|
NEUROFIBROMATOSIS, TYPE I
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000020515.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 21, 2015 |
Comment on evidence:
A C-to-T transition changing arginine-1947 to a stop codon (R1947X) in the NF1 gene has been described in multiple Caucasian and Japanese families with neurofibromatosis … (more)
A C-to-T transition changing arginine-1947 to a stop codon (R1947X) in the NF1 gene has been described in multiple Caucasian and Japanese families with neurofibromatosis type I (NF1; 162200), suggesting that this codon, CGA, is a hotspot for mutation, presumably because it contains a CpG dinucleotide. (Numbering of codons is based on Marchuk et al. (1991).) The mutation was described in 3 unrelated Caucasians (Ainsworth et al., 1993; Cawthon et al., 1990; Estivill et al., 1991); at least 2 of these cases were sporadic. Horiuchi et al. (1994) reported the same mutation in 2 unrelated familial cases of NF1. That these represented independent mutations was indicated by the fact that in the 2 families the affected individuals differed with regard to a polymorphism located within the NF1 gene. The frequency of the arg1947-to-ter mutation may be as high as 8% in Japanese and at least 1% in Caucasians. Studying one of the patients with the arg1947-to-ter mutation, Horiuchi et al. (1994) showed that both the normal and the mutant allele were transcribed in a lymphoblastoid cell line. Heim et al. (1994) stated that the R1947X mutation had been reported in 6 unrelated patients with NF1. Lazaro et al. (1995) presented 2 further cases of the R1947X mutation in the NF1 gene. They stated that a total of 9 cases of the R1947X mutation had been reported, giving a frequency of about 2%. They developed an allele-specific oligonucleotide hybridization assay for the efficient screening of a large number of samples for this relatively common recurrent mutation. In a sample of 56 unrelated Korean patients with NF1, Park et al. (2000) identified 1 with the R1947X mutation. (less)
|
|
|
Pathogenic
(Mar 03, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Neurofibromatosis, type 1
Affected status: yes
Allele origin:
germline
|
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000692361.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
|
|
|
Pathogenic
(Oct 23, 2023)
|
no assertion criteria provided
Method: clinical testing
|
Neurofibromatosis-Noonan syndrome
Affected status: yes
Allele origin:
germline
|
Diagnostics Centre, Carl Von Ossietzky University Oldenburg
Accession: SCV005049561.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
Comment:
The variant NF1:c.5839C>T, p.(Arg1968*), which is located in the coding exon 40 of the NF1 gene, results from a cytosine-to-thymine substitution at nucleotide position c.5839. … (more)
The variant NF1:c.5839C>T, p.(Arg1968*), which is located in the coding exon 40 of the NF1 gene, results from a cytosine-to-thymine substitution at nucleotide position c.5839. The arginine at protein position 1968 is replaced by a stop codon at the translational level. The variant affects and exon (40/58) that is present in biologically relevant transcripts and is predicted to cause protein truncation/absent due to non-sense mediated decay.The variant is classified as rare in the overall population (allele frequency= 0.000001859 in gnomAD v4.1.0). The variant has been consistenly classified as Pathogenic on 17 entries in ClinVar (ClinVarID: 343). In several publications, the variant has been reported as causative for neurofibromatosis (PMID: 2114220, 7649559, 12807981,10076878). Similar to previous report, the variant was detected de novo. In summary, the variant is classified as Pathogenic. (less)
Number of individuals with the variant: 1
Age: 10-19 years
Sex: female
|
|
| click to load more click to collapse | |||||
Citation text
Cawthon, R. M., Viskochil, D., O'Connell, P., Buchberg, A., Andersen, L., Wallace, M., Marchuk, D., Stevens, J., Culver, M., Xu, G., Collins, F. S., Jenkins, N., Copeland, N., White, R. Identification and characterization of several genes between or nearby neurofibromatosis type I translocation breakpoint. (Abstract) Am. J. Hum. Genet. 47 (suppl.): A109, 1990.
Comment:
ACMG criteria used to clasify this variant: PVS1, PM1, PM2, PS4
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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15146469, 16944272, 22913777, 8845843, 9042399, 25525159, 9195229, 24232412, 1757093, 18546366, 12552569, 27322474, 22155606, 7649559, 11015700, 10721668, 7903661, 8385067, 9101300, 2114220, 26969325, 10076878, 21354044, 29178821, 28124441, 19142971, 16117786, 30290804, 31533797, 31370276, 33443663)
Comment:
The NF1 c.5902C>T variant is predicted to result in premature protein termination (p.Arg1968*). This variant, referred to as c.5839C>T (p.Arg1947*) in an alternate transcript (NM_000267.3), has been reported in multiple individuals with neurofibromatosis type 1 (see for example - Fashold et al. 2000. PubMed ID: 10712197; de Luca et al. 2004. PubMed ID: 15146469). To our knowledge, 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/343/). Nonsense variants in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Arg1947*) 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 clinical features of neurofibromatosis type 1 (PMID: 2114220, 7649559, 7903661, 8069310, 8385067, 10076878; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as 1087C>T and c.5902C>T (Arg1968Ter). ClinVar contains an entry for this variant (Variation ID: 343). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.5839C>T (p.R1947*) alteration, located in exon 39 (coding exon 39) of the NF1 gene, consists of a C to T substitution at nucleotide position 5839. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 1947. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This pathogenic mutation (also known as p.R1968* (c.5902C>T) in the NM_001042492 isoform) has been described as a recurring mutation in individuals meeting diagnostic criteria for Neurofibromatosis type 1 (NF1) (Cawthon, 1990; Fahsold, 2000; Ars, 2003; Stewart, 2014; Hutter, 2016). In addition, it is located in a mutational hotspot of CpG dinucloetide repeats and methylated site of the gene (Andrews, 1996). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
NF1: PVS1, PM2
Comment:
The p.R1968* pathogenic mutation (also known as c.5902C>T) located in coding exon 40 of the NF1 gene, results from a C to T substitution at nucleotide position 5902. This changes the amino acid from an arginine to a stop codon within coding exon 40. This pathogenic mutation has been described as a recurring mutation in individuals with neurofibromatosis type 1 (Ars E et al. J. Med. Genet. 2003; 40:e82, Fahsold R et al. Am. J. Hum. Genet. 2000; 66:790-818). In addtition, it is located in a mutational hotspot of CpG dinucloetide repeats and methylated site of the gene (Andrews JD et al. Hum. Mol. Genet. 1996, 5:503-7). In addition to the clinical data presented in the literature, since premature stop codons 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). This pathogenic mutation is also known as p.R1947* (c.5839C>T) in the literature.
Comment:
The variant NF1:c.5839C>T, p.(Arg1968*), which is located in the coding exon 40 of the NF1 gene, results from a cytosine-to-thymine substitution at nucleotide position c.5839. The arginine at protein position 1968 is replaced by a stop codon at the translational level. The variant affects and exon (40/58) that is present in biologically relevant transcripts and is predicted to cause protein truncation/absent due to non-sense mediated decay.The variant is classified as rare in the overall population (allele frequency= 0.000001859 in gnomAD v4.1.0). The variant has been consistenly classified as Pathogenic on 17 entries in ClinVar (ClinVarID: 343). In several publications, the variant has been reported as causative for neurofibromatosis (PMID: 2114220, 7649559, 12807981,10076878). Similar to previous report, the variant was detected de novo. In summary, the variant is classified as Pathogenic.
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. |
Comment:
ACMG criteria used to clasify this variant: PVS1, PM1, PM2, PS4
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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15146469, 16944272, 22913777, 8845843, 9042399, 25525159, 9195229, 24232412, 1757093, 18546366, 12552569, 27322474, 22155606, 7649559, 11015700, 10721668, 7903661, 8385067, 9101300, 2114220, 26969325, 10076878, 21354044, 29178821, 28124441, 19142971, 16117786, 30290804, 31533797, 31370276, 33443663)
Comment:
The NF1 c.5902C>T variant is predicted to result in premature protein termination (p.Arg1968*). This variant, referred to as c.5839C>T (p.Arg1947*) in an alternate transcript (NM_000267.3), has been reported in multiple individuals with neurofibromatosis type 1 (see for example - Fashold et al. 2000. PubMed ID: 10712197; de Luca et al. 2004. PubMed ID: 15146469). To our knowledge, 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/343/). Nonsense variants in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Arg1947*) 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 clinical features of neurofibromatosis type 1 (PMID: 2114220, 7649559, 7903661, 8069310, 8385067, 10076878; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as 1087C>T and c.5902C>T (Arg1968Ter). ClinVar contains an entry for this variant (Variation ID: 343). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.5839C>T (p.R1947*) alteration, located in exon 39 (coding exon 39) of the NF1 gene, consists of a C to T substitution at nucleotide position 5839. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 1947. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This pathogenic mutation (also known as p.R1968* (c.5902C>T) in the NM_001042492 isoform) has been described as a recurring mutation in individuals meeting diagnostic criteria for Neurofibromatosis type 1 (NF1) (Cawthon, 1990; Fahsold, 2000; Ars, 2003; Stewart, 2014; Hutter, 2016). In addition, it is located in a mutational hotspot of CpG dinucloetide repeats and methylated site of the gene (Andrews, 1996). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
NF1: PVS1, PM2
Comment:
The p.R1968* pathogenic mutation (also known as c.5902C>T) located in coding exon 40 of the NF1 gene, results from a C to T substitution at nucleotide position 5902. This changes the amino acid from an arginine to a stop codon within coding exon 40. This pathogenic mutation has been described as a recurring mutation in individuals with neurofibromatosis type 1 (Ars E et al. J. Med. Genet. 2003; 40:e82, Fahsold R et al. Am. J. Hum. Genet. 2000; 66:790-818). In addtition, it is located in a mutational hotspot of CpG dinucloetide repeats and methylated site of the gene (Andrews JD et al. Hum. Mol. Genet. 1996, 5:503-7). In addition to the clinical data presented in the literature, since premature stop codons 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). This pathogenic mutation is also known as p.R1947* (c.5839C>T) in the literature.
Comment:
The variant NF1:c.5839C>T, p.(Arg1968*), which is located in the coding exon 40 of the NF1 gene, results from a cytosine-to-thymine substitution at nucleotide position c.5839. The arginine at protein position 1968 is replaced by a stop codon at the translational level. The variant affects and exon (40/58) that is present in biologically relevant transcripts and is predicted to cause protein truncation/absent due to non-sense mediated decay.The variant is classified as rare in the overall population (allele frequency= 0.000001859 in gnomAD v4.1.0). The variant has been consistenly classified as Pathogenic on 17 entries in ClinVar (ClinVarID: 343). In several publications, the variant has been reported as causative for neurofibromatosis (PMID: 2114220, 7649559, 12807981,10076878). Similar to previous report, the variant was detected de novo. In summary, the variant is classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Identification and characterization of NF1 and non-NF1 congenital pseudarthrosis of the tibia based on germline NF1 variants: genetic and clinical analysis of 75 patients. | Zhu G | Orphanet journal of rare diseases | 2019 | PMID: 31533797 |
| 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 |
| Recurrent mutations in the NF1 gene are common among neurofibromatosis type 1 patients. | Ars E | Journal of medical genetics | 2003 | PMID: 12807981 |
| A nonsense mutation at Arg-1947 in the NF1 gene in a case of neurofibromatosis type 1 in a Korean patient. | Park KC | Journal of human genetics | 2000 | PMID: 10721668 |
| 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 |
| Two independent mutations in a family with neurofibromatosis type 1 (NF1). | Klose A | American journal of medical genetics | 1999 | PMID: 10076878 |
| Site and sequence specific DNA methylation in the neurofibromatosis (NF1) gene includes C5839T: the site of the recurrent substitution mutation in exon 31. | Andrews JD | Human molecular genetics | 1996 | PMID: 8845843 |
| Two further cases of mutation R1947X in the NF1 gene: screening for a relatively common recurrent mutation. | Lázaro C | Human genetics | 1995 | PMID: 7649559 |
| Characterization of four mutations in the neurofibromatosis type 1 gene by denaturing gradient gel electrophoresis (DGGE). | Valero MC | Human molecular genetics | 1994 | PMID: 8069310 |
| Nonsense mutations at Arg-1947 in two cases of familial neurofibromatosis type 1 in Japanese. | Horiuchi T | Human genetics | 1994 | PMID: 7903661 |
| Screening for truncated NF1 proteins. | Heim RA | Nature genetics | 1994 | PMID: 7874161 |
| Identification and characterization of sporadic and inherited mutations in exon 31 of the neurofibromatosis (NF1) gene. | Ainsworth PJ | Human genetics | 1993 | PMID: 8385067 |
| cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product. | Marchuk DA | Genomics | 1991 | PMID: 1783401 |
| Recurrence of a nonsense mutation in the NF1 gene causing classical neurofibromatosis type 1. | Estivill X | Human genetics | 1991 | PMID: 1757093 |
| A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. | Cawthon RM | Cell | 1990 | PMID: 2114220 |
| Cawthon, R. M., Viskochil, D., O'Connell, P., Buchberg, A., Andersen, L., Wallace, M., Marchuk, D., Stevens, J., Culver, M., Xu, G., Collins, F. S., Jenkins, N., Copeland, N., White, R. Identification and characterization of several genes between or nearby neurofibromatosis type I translocation breakpoint. (Abstract) Am. J. Hum. Genet. 47 (suppl.): A109, 1990. | - | - | - | - |
| click to load more click to collapse | ||||
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
|
Jul 31, 2024 | RCV004668704.1 |
Submissions - Somatic
|
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
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. |
More information
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. |
|---|
|
Likely oncogenic
(Jul 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Neoplasm
Affected status: unknown
Allele origin:
somatic
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005093976.1
First In ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
|
Citation text
Cawthon, R. M., Viskochil, D., O'Connell, P., Buchberg, A., Andersen, L., Wallace, M., Marchuk, D., Stevens, J., Culver, M., Xu, G., Collins, F. S., Jenkins, N., Copeland, N., White, R. Identification and characterization of several genes between or nearby neurofibromatosis type I translocation breakpoint. (Abstract) Am. J. Hum. Genet. 47 (suppl.): A109, 1990.
Comment:
ACMG criteria used to clasify this variant: PVS1, PM1, PM2, PS4
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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15146469, 16944272, 22913777, 8845843, 9042399, 25525159, 9195229, 24232412, 1757093, 18546366, 12552569, 27322474, 22155606, 7649559, 11015700, 10721668, 7903661, 8385067, 9101300, 2114220, 26969325, 10076878, 21354044, 29178821, 28124441, 19142971, 16117786, 30290804, 31533797, 31370276, 33443663)
Comment:
The NF1 c.5902C>T variant is predicted to result in premature protein termination (p.Arg1968*). This variant, referred to as c.5839C>T (p.Arg1947*) in an alternate transcript (NM_000267.3), has been reported in multiple individuals with neurofibromatosis type 1 (see for example - Fashold et al. 2000. PubMed ID: 10712197; de Luca et al. 2004. PubMed ID: 15146469). To our knowledge, 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/343/). Nonsense variants in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Arg1947*) 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 clinical features of neurofibromatosis type 1 (PMID: 2114220, 7649559, 7903661, 8069310, 8385067, 10076878; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as 1087C>T and c.5902C>T (Arg1968Ter). ClinVar contains an entry for this variant (Variation ID: 343). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.5839C>T (p.R1947*) alteration, located in exon 39 (coding exon 39) of the NF1 gene, consists of a C to T substitution at nucleotide position 5839. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 1947. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This pathogenic mutation (also known as p.R1968* (c.5902C>T) in the NM_001042492 isoform) has been described as a recurring mutation in individuals meeting diagnostic criteria for Neurofibromatosis type 1 (NF1) (Cawthon, 1990; Fahsold, 2000; Ars, 2003; Stewart, 2014; Hutter, 2016). In addition, it is located in a mutational hotspot of CpG dinucloetide repeats and methylated site of the gene (Andrews, 1996). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
NF1: PVS1, PM2
Comment:
The p.R1968* pathogenic mutation (also known as c.5902C>T) located in coding exon 40 of the NF1 gene, results from a C to T substitution at nucleotide position 5902. This changes the amino acid from an arginine to a stop codon within coding exon 40. This pathogenic mutation has been described as a recurring mutation in individuals with neurofibromatosis type 1 (Ars E et al. J. Med. Genet. 2003; 40:e82, Fahsold R et al. Am. J. Hum. Genet. 2000; 66:790-818). In addtition, it is located in a mutational hotspot of CpG dinucloetide repeats and methylated site of the gene (Andrews JD et al. Hum. Mol. Genet. 1996, 5:503-7). In addition to the clinical data presented in the literature, since premature stop codons 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). This pathogenic mutation is also known as p.R1947* (c.5839C>T) in the literature.
Comment:
The variant NF1:c.5839C>T, p.(Arg1968*), which is located in the coding exon 40 of the NF1 gene, results from a cytosine-to-thymine substitution at nucleotide position c.5839. The arginine at protein position 1968 is replaced by a stop codon at the translational level. The variant affects and exon (40/58) that is present in biologically relevant transcripts and is predicted to cause protein truncation/absent due to non-sense mediated decay.The variant is classified as rare in the overall population (allele frequency= 0.000001859 in gnomAD v4.1.0). The variant has been consistenly classified as Pathogenic on 17 entries in ClinVar (ClinVarID: 343). In several publications, the variant has been reported as causative for neurofibromatosis (PMID: 2114220, 7649559, 12807981,10076878). Similar to previous report, the variant was detected de novo. In summary, the variant is classified as Pathogenic.
Citations for somatic classification of this variant
Help| There are no citations for somatic classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs137854552 ...
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 Nov 10, 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.