ClinVar Genomic variation as it relates to human health
NM_001042492.3(NF1):c.574C>T (p.Arg192Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001042492.3(NF1):c.574C>T (p.Arg192Ter)
Variation ID: 40093 Accession: VCV000040093.91
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q11.2 17: 31169985 (GRCh38) [ NCBI UCSC ] 17: 29497003 (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 May 12, 2024 Dec 31, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001042492.3:c.574C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001035957.1:p.Arg192Ter nonsense NM_000267.3:c.574C>T NP_000258.1:p.Arg192Ter nonsense NM_001128147.3:c.574C>T NP_001121619.1:p.Arg192Ter nonsense NC_000017.11:g.31169985C>T NC_000017.10:g.29497003C>T NG_009018.1:g.80009C>T LRG_214:g.80009C>T LRG_214t1:c.574C>T LRG_214p1:p.Arg192Ter LRG_214t2:c.574C>T LRG_214p2:p.Arg192Ter - Protein change
- R192*
- Other names
- -
- Canonical SPDI
- NC_000017.11:31169984: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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00000
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 |
13562 | 13969 |
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 (12) |
criteria provided, multiple submitters, no conflicts
|
Dec 31, 2023 | RCV000033171.39 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Mar 28, 2022 | RCV000442381.32 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jan 1, 2017 | RCV000626737.9 | |
Likely pathogenic (1) |
no assertion criteria provided
|
- | RCV001003806.8 | |
Pathogenic (1) |
criteria provided, single submitter
|
Apr 18, 2022 | RCV002310996.8 | |
See cases
|
Pathogenic (1) |
criteria provided, single submitter
|
Mar 1, 2023 | RCV003231110.8 |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 14, 2022 | RCV003460540.1 |
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
(Nov 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Neurofibromatosis, type 1
Affected status: yes
Allele origin:
germline
|
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781874.1
First in ClinVar: Jul 07, 2018 Last updated: Jul 07, 2018 |
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Neurofibromatosis, type 1
Affected status: yes
Allele origin:
unknown
|
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn
Accession: SCV000999356.1
First in ClinVar: Nov 29, 2019 Last updated: Nov 29, 2019 |
Number of individuals with the variant: 1
Clinical Features:
Eruptive xanthomas (present) , Downturned corners of mouth (present) , Cafe-au-lait spot (present) , Multiple cafe-au-lait spots (present) , Frontal bossing (present)
|
|
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: SCV001479214.1
First in ClinVar: Feb 13, 2021 Last updated: Feb 13, 2021 |
|
|
Pathogenic
(Apr 19, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV000842893.2
First in ClinVar: Mar 08, 2017 Last updated: Sep 19, 2021 |
Comment:
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with … (more)
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. (less)
|
|
Pathogenic
(Dec 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Neurofibromatosis, type 1
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002061777.3
First in ClinVar: Jan 22, 2022 Last updated: Aug 05, 2023 |
Comment:
PVS1, PS4, PP1, PM2_Supporting, PM6
|
|
Pathogenic
(Apr 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000581337.5
First in ClinVar: Jul 01, 2017 Last updated: Nov 29, 2022 |
Comment:
The p.R192* pathogenic mutation (also known as c.574C>T), located in coding exon 5 of the NF1 gene, results from a C to T substitution at … (more)
The p.R192* pathogenic mutation (also known as c.574C>T), located in coding exon 5 of the NF1 gene, results from a C to T substitution at nucleotide position 574. This changes the amino acid from an arginine to a stop codon within coding exon 5. This mutation has been identified in numerous individuals who meet clinical criteria for neurofibromatosis type 1 (NF1) (Toliat MR et al. Electrophoresis. 2000 Feb;21:541-4; Fahsold R et al. Am. J. Hum. Genet. 2000 Mar;66:790-818; De Luca A et al. Hum. Mutat. 2004 Jun;23:629; Lee MJ et al. Hum. Mutat. 2006 Aug;27:832; Cali F et. al Eur J Med Genet. 2017 Feb;60(2):93-99; Wu-Chou YH et al. J. Biomed. Sci. 2018 Oct;25(1):72). 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
(Mar 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
see cases
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University Hospital Muenster
Accession: SCV003929499.1
First in ClinVar: Jun 10, 2023 Last updated: Jun 10, 2023 |
Comment:
ACMG categories: PVS1,PM1,PP5
Number of individuals with the variant: 1
Clinical Features:
Nevus flammeus (present) , Cafe-au-lait spot (present)
Age: 0-9 years
Sex: female
Tissue: blood
|
|
Pathogenic
(Oct 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Juvenile myelomonocytic leukemia
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004190785.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Pathogenic
(Jan 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Axillary freckling
Focal T2 hyperintense basal ganglia lesion Cafe au lait spots, multiple
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000747440.1
First in ClinVar: May 12, 2018 Last updated: May 12, 2018 |
|
|
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: SCV000588698.2
First in ClinVar: Aug 13, 2017 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: SCV002561585.1
First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022 |
|
|
Pathogenic
(May 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Neurofibromatosis, type 1
Affected status: yes
Allele origin:
unknown
|
Institute of Medical Genetics, University of Zurich
Accession: SCV002569050.2
First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023 |
|
|
Pathogenic
(Sep 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Neurofibromatosis, type 1
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002581880.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PS4_MOD, PM2_SUP
|
Number of individuals with the variant: 1
Sex: male
|
|
Pathogenic
(Feb 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Neurofibromatosis, type 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768237.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurofibromatosis type 1 (MIM#162200). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with neurofibromatosis type 1 (PMID: 27838393). (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
Pathogenic
(Mar 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000521057.8
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; This … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 10726756, 15846561, 19142971, 17353900, 17406642, 10712197, 10862084, 12095621, 15146469, 27625798, 25525159, 26056819, 27838393, 28529006, 31347283, 31717729, 30613976, 32581362, 31370276, 31776437) (less)
|
|
Pathogenic
(Apr 19, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002774392.2
First in ClinVar: Dec 31, 2022 Last updated: Jan 06, 2024 |
Comment:
The NF1 c.574C>T (p.Arg192*) variant causes the premature termination of NF1 protein synthesis. This variant has been reported in the published literature in multiple individuals … (more)
The NF1 c.574C>T (p.Arg192*) variant causes the premature termination of NF1 protein synthesis. This variant has been reported in the published literature in multiple individuals and families with NF1 in the published literature (PMID: 27838393 (2017), 26056819 (2015), 21278392 (2011), 19142971 (2009), 17406642 (2007), 16835897 (2006), 15146469 (2004), 10862084 (2000), 10726756 (2000), 10712197 (2000)). The frequency of this variant in the general population, 0.000004 (1/250636 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. (less)
|
|
Pathogenic
(Dec 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Neurofibromatosis, type 1
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000218634.12
First in ClinVar: Mar 29, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg192*) 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.Arg192*) in the NF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This variant is present in population databases (rs397514641, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10712197, 10726756, 15146469, 16835897, 21278392, 26056819, 27838393). ClinVar contains an entry for this variant (Variation ID: 40093). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Feb 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001746520.15
First in ClinVar: Jul 10, 2021 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
|
|
Pathogenic
(Aug 01, 2007)
|
no assertion criteria provided
Method: literature only
|
NEUROFIBROMATOSIS, TYPE I
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000056953.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 21, 2015 |
Comment on evidence:
In a girl with aniridia, microphthalmia, microcephaly, and cafe-au-lait macules, Henderson et al. (2007) identified heterozygosity for a 574C-T transition in exon 4b of the … (more)
In a girl with aniridia, microphthalmia, microcephaly, and cafe-au-lait macules, Henderson et al. (2007) identified heterozygosity for a 574C-T transition in exon 4b of the NF1 gene, resulting in an arg192-to-ter (R192X) substitution, as well as heterozygous mutations in the PAX6 (R38W; 607108.0026) and OTX2 (Y179X; 600037.0004) genes. Her mother, who carried the NF1 and PAX6 mutations, had NF1 (162200) with the typical eye defects of retinal fibroma, optic nerve glioma, and gross Lisch nodules on the iris; in addition, although her eyes were of normal size, she had eyes were of normal size, she had small corneas, and also had cataracts, optic nerve hypoplasia, nystagmus, and mild iris stromal hypoplasia with normal-sized pupils. The proband's father, who had multiple ocular defects (MCOPS5; 610125), had previously been studied by Ragge et al. (2005) and was heterozygous for the OTX2 nonsense mutation. Henderson et al. (2007) noted that the proband's phenotype was surprisingly mild, given that mutations in PAX6, OTX2, or NF1 can cause a variety of severe developmental defects. (less)
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001970884.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Neurofibromatosis
Juvenile myelomonocytic leukemia
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001162255.1
First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020 |
Number of individuals with the variant: 1
Sex: female
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001963067.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
|
Pathogenic
(Apr 01, 2023)
|
no assertion criteria provided
Method: clinical testing
|
Neurofibromatosis, type 1
Affected status: yes
Allele origin:
germline
|
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)
Accession: SCV003927940.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
|
|
click to load more click to collapse |
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
Mutation spectrum of NF1 gene in Italian patients with neurofibromatosis type 1 using Ion Torrent PGM™ platform. | Calì F | European journal of medical genetics | 2017 | PMID: 27838393 |
Molecular Characterization of NF1 and Neurofibromatosis Type 1 Genotype-Phenotype Correlations in a Chinese Population. | Zhang J | Scientific reports | 2015 | PMID: 26056819 |
NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience. | Sabbagh A | Human mutation | 2013 | PMID: 23913538 |
A molecular analysis of individuals with neurofibromatosis type 1 (NF1) and optic pathway gliomas (OPGs), and an assessment of genotype-phenotype correlations. | Sharif S | Journal of medical genetics | 2011 | PMID: 21278392 |
Germline and somatic NF1 mutations in sporadic and NF1-associated malignant peripheral nerve sheath tumours. | Bottillo I | The Journal of pathology | 2009 | PMID: 19142971 |
Inherited PAX6, NF1 and OTX2 mutations in a child with microphthalmia and aniridia. | Henderson RA | European journal of human genetics : EJHG | 2007 | PMID: 17406642 |
Identification of forty-five novel and twenty-three known NF1 mutations in Chinese patients with neurofibromatosis type 1. | Lee MJ | Human mutation | 2006 | PMID: 16835897 |
Heterozygous mutations of OTX2 cause severe ocular malformations. | Ragge NK | American journal of human genetics | 2005 | PMID: 15846561 |
Novel and recurrent mutations in the NF1 gene in Italian patients with neurofibromatosis type 1. | De Luca A | Human mutation | 2004 | PMID: 15146469 |
Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. | Messiaen LM | Human mutation | 2000 | PMID: 10862084 |
Analysis of the NF1 gene by temperature gradient gel electrophoresis reveals a high incidence of mutations in exon 4b. | Toliat MR | Electrophoresis | 2000 | PMID: 10726756 |
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 |
click to load more click to collapse |
Text-mined citations for rs397514641 ...
HelpRecord last updated May 27, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.