VCV000187722.40 - ClinVar

NM_001042492.3(NF1):c.910C>T (p.Arg304Ter)

Germline

Classification

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.

(21)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001042492.3(NF1):c.910C>T (p.Arg304Ter)

Variation ID: 187722 Accession: VCV000187722.40

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q11.2 17: 31200443 (GRCh38) [ NCBI UCSC ] 17: 29527461 (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	Mar 24, 2015	Nov 17, 2024	Nov 12, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001042492.3:c.910C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001035957.1:p.Arg304Ter	nonsense
NM_000267.3:c.910C>T	NP_000258.1:p.Arg304Ter	nonsense
NM_001128147.3:c.910C>T	NP_001121619.1:p.Arg304Ter	nonsense
NC_000017.11:g.31200443C>T
NC_000017.10:g.29527461C>T
NG_009018.1:g.110467C>T
LRG_214:g.110467C>T
LRG_214t1:c.910C>T	LRG_214p1:p.Arg304Ter
LRG_214t2:c.910C>T	LRG_214p2:p.Arg304Ter

... more HGVS ... less HGVS

Protein change

R304*

Other names

Canonical SPDI

NC_000017.11:31200442:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA198406 dbSNP: rs786203950 VarSome

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
Gene	OMIM	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	14135	14574

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.
Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Dec 26, 2014	RCV000167474.1
Neurofibromatosis, type 1	Pathogenic (11)	criteria provided, multiple submitters, no conflicts	Nov 12, 2024	RCV000468520.23
not specified	Pathogenic (1)	criteria provided, single submitter	Aug 15, 2018	RCV000508304.9
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Mar 11, 2024	RCV000579282.13
Juvenile myelomonocytic leukemia	Pathogenic (1)	criteria provided, single submitter	Feb 12, 2020	RCV001294062.1
Café-au-lait macules with pulmonary stenosis Juvenile myelomonocytic leukemia Neurofibromatosis, familial spinal Neurofibromatosis, type 1 Neurofibromatosis-Noonan syndrome	Pathogenic (1)	criteria provided, single submitter	Mar 12, 2022	RCV002498830.1
NF1-related disorder	Pathogenic (1)	criteria provided, single submitter	Feb 15, 2023	RCV004552933.1

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 (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 1 Affected status: yes Allele origin: germline	Center for Human Genetics, Inc, Center for Human Genetics, Inc Accession: SCV000781883.1 First in ClinVar: Jul 07, 2018 Last updated: Jul 07, 2018
Pathogenic (Dec 26, 2014)	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (10/2015)) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000218330.5 First in ClinVar: Mar 24, 2015 Last updated: Mar 24, 2015	Comment: The p.R304* pathogenic mutation (also known as c.910C>T), located in coding exon 9 of the NF1 gene, results from a C to T substitution at … (more) The p.R304* pathogenic mutation (also known as c.910C>T), located in coding exon 9 of the NF1 gene, results from a C to T substitution at nucleotide position 910. This changes the amino acid from an arginine to a stop codon within coding exon 9. This mutation has been observed in multiple individuals meeting clinical diagnostic criteria for NF1 (De Luca, A et al. Hum Mutat. 2004 Jun;23(6):629; Fahsold, R et al. Am J Hum Genet. 2000 Mar;66(3):790-818; Upadhyaya, M et al. Hum Mutat. 2008 Aug;29(8):E103-11; Ko, JM et al. Pediatr Neurol. 2013 Jun;48(6):447-53). 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). (less) Number of individuals with the variant: 1
Pathogenic (Oct 26, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 1 Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV001479110.1 First in ClinVar: Feb 13, 2021 Last updated: Feb 13, 2021
Pathogenic (Feb 12, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Juvenile myelomonocytic leukemia Affected status: yes Allele origin: unknown	Baylor Genetics Study: CSER-TexasKidsCanSeq Accession: SCV001482855.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021	Publications: PubMed (4) PubMed: 9463322‚ 26509978‚ 10874316‚ 25525159 Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 9463322, 26509978, 10874316, … (more) This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 9463322, 26509978, 10874316, 25525159] (less)
Pathogenic (Jun 06, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 1 Affected status: yes Allele origin: germline	Center of Genomic medicine, Geneva, University Hospital of Geneva Accession: SCV000590893.1 First in ClinVar: Apr 17, 2017 Last updated: Apr 17, 2017	Age: 10-19 years Sex: female
Pathogenic (Aug 15, 2018)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000604459.2 First in ClinVar: Sep 30, 2017 Last updated: Feb 09, 2020	Comment: The NF1 c.910C>T; p.Arg304Ter variant (rs786203950) has been described in several individuals with neurofibromatosis type 1 (NF1) (see link below, Ko 2013, Upadhyaya 2008). It … (more) The NF1 c.910C>T; p.Arg304Ter variant (rs786203950) has been described in several individuals with neurofibromatosis type 1 (NF1) (see link below, Ko 2013, Upadhyaya 2008). It is reported as pathogenic in ClinVar (Variation ID: 187722) and observed on only 1 allele in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. References: Link to NF1 LOVD Database for p.Arg304Ter: https://grenada.lumc.nl/LOVD2/mendelian_genes/variants.php?select_db=NF1&action=search_all&search_Variant%2FDNA=c.910C%3ET Ko JM et al. (2013) Mutation spectrum of NF1 and clinical characteristics in 78 Korean patients with neurofibromatosis type 1. Pediatr Neurol. 48(6):447-53. Upadhyaya M et al. (2008) Germline and somatic NF1 gene mutations in plexiform neurofibromas. Hum Mutat. 29(8):E103-11. (less)
Pathogenic (Dec 20, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 1 Affected status: yes Allele origin: germline	Medical Genetics, University of Parma Accession: SCV001218910.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Pathogenic (Jan 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 1 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368730.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS3.
Pathogenic (Jan 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 1 Affected status: yes Allele origin: germline	DASA Accession: SCV002061224.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022	Publications: PubMed (5) PubMed: 23668869‚ 16786508‚ 23913538‚ 10862084‚ 9463322 Comment: The c.910C>T;p.(Arg304) variant creates a premature translational stop signal in the NF1 gene. It is expected to result in an absent or disrupted protein product … (more) The c.910C>T;p.(Arg304) variant creates a premature translational stop signal in the NF1 gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 187722; PMID: 23668869; 16786508; 23913538; 10862084; 9463322) - PS4. This variant is not present in population databases (rs786203950, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. (less) Number of individuals with the variant: 1 Sex: female Geographic origin: Brazil
Pathogenic (Mar 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 1 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002561612.1 First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022
Pathogenic (Jun 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 1 Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003807719.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PP4 Number of individuals with the variant: 1 Clinical Features: Hepatic hemangioma (present) , Glaucoma (present) , Cafe-au-lait spot (present) , Lumbar hyperlordosis (present) , Plexiform neurofibroma (present) , Gastroesophageal reflux (present) , Scoliosis (present) … (more) Hepatic hemangioma (present) , Glaucoma (present) , Cafe-au-lait spot (present) , Lumbar hyperlordosis (present) , Plexiform neurofibroma (present) , Gastroesophageal reflux (present) , Scoliosis (present) , Migraine (present) , Seizure (present) (less) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Feb 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NF1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004118366.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The NF1 c.910C>T variant is predicted to result in premature protein termination (p.Arg304). This variant has been reported in multiple individuals with neurofibromatosis type 1 … (more) The NF1 c.910C>T variant is predicted to result in premature protein termination (p.Arg304). This variant has been reported in multiple individuals with neurofibromatosis type 1 (see for example - Upadhyaya et al. 2008. PubMed ID: 18484666; Palma Milla et al. 2018. PubMed ID: 30014477). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-29527461-C-T). Nonsense variants in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001446786.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Neurofibroma (present) Sex: female
Pathogenic (Mar 12, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV002808718.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Sep 23, 2016)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004222184.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (18) PubMed: 23913538‚ 9463322‚ 18484666‚ 23668869‚ 14722917‚ 20601955‚ 22108604‚ 23781326‚ 12112660‚ 17295913‚ 10712197‚ 19935827‚ 12807981‚ 26509978‚ 24789688‚ 10862084‚ 11431704‚ 12095621 Comment: The NF1 c.910C>T (p.Arg304) variant causes the premature termination of NF1 protein synthesis. This variant has been reported in the published literature in individuals with … (more) The NF1 c.910C>T (p.Arg304) variant causes the premature termination of NF1 protein synthesis. This variant has been reported in the published literature in individuals with neurofibromatosis 1 (NF1) (PMID: 23913538 (2013), 23668869 (2013), 22108604 (2011), 19935827 (2010), 18484666 (2008), 14722917 (2004), 12807981 (2003), 12112660 (2002), 10862084 (2000), 10712197 (2000)). Published functional studies show that this variant results in skipping of exon 7 and produces an aberrant transcript (PMID: 17295913 (2007), 26509978 (2015), 9463322 (1998)). The frequency of this variant in the general population, 0.000004 (1/251414 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 (Jan 10, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Neurofibromatosis, type 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000542003.9 First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024	Publications: PubMed (8) PubMed: 28492532‚ 10712197‚ 23913538‚ 10862084‚ 16786508‚ 23668869‚ 9463322‚ 10874316 Comment: This sequence change creates a premature translational stop signal (p.Arg304) 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.Arg304) 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 (rs786203950, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with neurofibromatosis, type 1 (PMID: 10862084, 16786508, 23668869, 23913538). ClinVar contains an entry for this variant (Variation ID: 187722). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects NF1 function (PMID: 9463322, 10874316). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 11, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000680718.7 First in ClinVar: Feb 13, 2018 Last updated: Sep 16, 2024	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 … (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: 26509978, 27838393, 29695767, 16786508, 34418705, 29922827, 34427956, 25525159, 17295913, 12057013, 12095621, 23668869, 18484666, 23781326, 10712197, 28247034, 29680440, 23913538, 30014477, 30290804, 12112660, 9463322, 10862084, 10874316, 31776437, 33877690, 34308104) (less)
Pathogenic (Nov 12, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis type 1 Affected status: yes Allele origin: germline	NHS Central & South Genomic Laboratory Hub Accession: SCV005395911.1 First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001959590.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Oct 29, 2017)	no assertion criteria provided Method: clinical testing	Neurofibromatosis, type 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: inherited	Coyote Medical Laboratory (Beijing), Coyote Accession: SCV001441284.1 First in ClinVar: Nov 06, 2020 Last updated: Nov 06, 2020	Number of individuals with the variant: 1 Clinical Features: Cafe-au-lait spot (present) , Lower limb asymmetry (present) , Hemihypertrophy (present) , Neurofibromas (present) Family history: yes Secondary finding: no Method: exome sequencing with trio,and validation by sanger sequencing Testing laboratory: Coyote Medical Laboratory (Beijing)
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: SCV001966481.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
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Comment:

The p.R304* pathogenic mutation (also known as c.910C>T), located in coding exon 9 of the NF1 gene, results from a C to T substitution at nucleotide position 910. This changes the amino acid from an arginine to a stop codon within coding exon 9. This mutation has been observed in multiple individuals meeting clinical diagnostic criteria for NF1 (De Luca, A et al. Hum Mutat. 2004 Jun;23(6):629; Fahsold, R et al. Am J Hum Genet. 2000 Mar;66(3):790-818; Upadhyaya, M et al. Hum Mutat. 2008 Aug;29(8):E103-11; Ko, JM et al. Pediatr Neurol. 2013 Jun;48(6):447-53). 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).

Comment:

The NF1 c.910C>T; p.Arg304Ter variant (rs786203950) has been described in several individuals with neurofibromatosis type 1 (NF1) (see link below, Ko 2013, Upadhyaya 2008). It is reported as pathogenic in ClinVar (Variation ID: 187722) and observed on only 1 allele in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. References: Link to NF1 LOVD Database for p.Arg304Ter: https://grenada.lumc.nl/LOVD2/mendelian_genes/variants.php?select_db=NF1&action=search_all&search_Variant%2FDNA=c.910C%3ET Ko JM et al. (2013) Mutation spectrum of NF1 and clinical characteristics in 78 Korean patients with neurofibromatosis type 1. Pediatr Neurol. 48(6):447-53. Upadhyaya M et al. (2008) Germline and somatic NF1 gene mutations in plexiform neurofibromas. Hum Mutat. 29(8):E103-11.

Comment:

The c.910C>T;p.(Arg304*) variant creates a premature translational stop signal in the NF1 gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 187722; PMID: 23668869; 16786508; 23913538; 10862084; 9463322) - PS4. This variant is not present in population databases (rs786203950, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic.

Comment:

The NF1 c.910C>T variant is predicted to result in premature protein termination (p.Arg304*). This variant has been reported in multiple individuals with neurofibromatosis type 1 (see for example - Upadhyaya et al. 2008. PubMed ID: 18484666; Palma Milla et al. 2018. PubMed ID: 30014477). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-29527461-C-T). Nonsense variants in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic.

Comment:

The NF1 c.910C>T (p.Arg304*) variant causes the premature termination of NF1 protein synthesis. This variant has been reported in the published literature in individuals with neurofibromatosis 1 (NF1) (PMID: 23913538 (2013), 23668869 (2013), 22108604 (2011), 19935827 (2010), 18484666 (2008), 14722917 (2004), 12807981 (2003), 12112660 (2002), 10862084 (2000), 10712197 (2000)). Published functional studies show that this variant results in skipping of exon 7 and produces an aberrant transcript (PMID: 17295913 (2007), 26509978 (2015), 9463322 (1998)). The frequency of this variant in the general population, 0.000004 (1/251414 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Arg304*) 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 (rs786203950, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with neurofibromatosis, type 1 (PMID: 10862084, 16786508, 23668869, 23913538). ClinVar contains an entry for this variant (Variation ID: 187722). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects NF1 function (PMID: 9463322, 10874316). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.

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 variant is associated with the following publications: (PMID: 26509978, 27838393, 29695767, 16786508, 34418705, 29922827, 34427956, 25525159, 17295913, 12057013, 12095621, 23668869, 18484666, 23781326, 10712197, 28247034, 29680440, 23913538, 30014477, 30290804, 12112660, 9463322, 10862084, 10874316, 31776437, 33877690, 34308104)

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Functional Analysis of Mutations in Exon 9 of NF1 Reveals the Presence of Several Elements Regulating Splicing.	Hernández-Imaz E	PloS one	2015	PMID: 26509978
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.	Xiong HY	Science (New York, N.Y.)	2015	PMID: 25525159
Fifty-four novel mutations in the NF1 gene and integrated analyses of the mutations that modulate splicing.	Xu W	International journal of molecular medicine	2014	PMID: 24789688
NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience.	Sabbagh A	Human mutation	2013	PMID: 23913538
Next-generation sequencing in the clinical genetic screening of patients with pheochromocytoma and paraganglioma.	Crona J	Endocrine connections	2013	PMID: 23781326
Mutation spectrum of NF1 and clinical characteristics in 78 Korean patients with neurofibromatosis type 1.	Ko JM	Pediatric neurology	2013	PMID: 23668869
Exploring the somatic NF1 mutational spectrum associated with NF1 cutaneous neurofibromas.	Thomas L	European journal of human genetics : EJHG	2012	PMID: 22108604
Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy.	Barretina J	Nature genetics	2010	PMID: 20601955
Modulation of aberrant NF1 pre-mRNA splicing by kinetin treatment.	Pros E	European journal of human genetics : EJHG	2010	PMID: 19935827
Germline and somatic NF1 gene mutations in plexiform neurofibromas.	Upadhyaya M	Human mutation	2008	PMID: 18484666
Functional analysis of splicing mutations in exon 7 of NF1 gene.	Bottillo I	BMC medical genetics	2007	PMID: 17295913
The heterogeneous nature of germline mutations in NF1 patients with malignant peripheral serve sheath tumours (MPNSTs).	Upadhyaya M	Human mutation	2006	PMID: 16786508
Characterization of the somatic mutational spectrum of the neurofibromatosis type 1 (NF1) gene in neurofibromatosis patients with benign and malignant tumors.	Upadhyaya M	Human mutation	2004	PMID: 14722917
Recurrent mutations in the NF1 gene are common among neurofibromatosis type 1 patients.	Ars E	Journal of medical genetics	2003	PMID: 12807981
Ten novel mutations in the human neurofibromatosis type 1 (NF1) gene in Italian patients.	Origone P	Human mutation	2002	PMID: 12112660
Quantification of NF1 transcripts reveals novel highly expressed splice variants.	Vandenbroucke I	FEBS letters	2002	PMID: 12095621
Mitotic recombination effects homozygosity for NF1 germline mutations in neurofibromas.	Serra E	Nature genetics	2001	PMID: 11431704
Three different premature stop codons lead to skipping of exon 7 in neurofibromatosis type I patients.	Wimmer K	Human mutation	2000	PMID: 10874316
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
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
Nearby stop codons in exons of the neurofibromatosis type 1 gene are disparate splice effectors.	Hoffmeyer S	American journal of human genetics	1998	PMID: 9463322
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Text-mined citations for rs786203950 ...

These 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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001042492.3(NF1):c.910C>T (p.Arg304Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs786203950 ...