VCV000280055.87 - ClinVar

NM_001042492.3(NF1):c.2446C>T (p.Arg816Ter)

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.

(18)

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.2446C>T (p.Arg816Ter)

Variation ID: 280055 Accession: VCV000280055.87

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q11.2 17: 31229061 (GRCh38) [ NCBI UCSC ] 17: 29556079 (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	Jul 1, 2017	Oct 20, 2024	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001042492.3:c.2446C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001035957.1:p.Arg816Ter	nonsense
NM_000267.3:c.2446C>T	NP_000258.1:p.Arg816Ter	nonsense
NC_000017.11:g.31229061C>T
NC_000017.10:g.29556079C>T
NG_009018.1:g.139085C>T
LRG_214:g.139085C>T
LRG_214t1:c.2446C>T	LRG_214p1:p.Arg816Ter
LRG_214t2:c.2446C>T	LRG_214p2:p.Arg816Ter

... more HGVS ... less HGVS

Protein change

R816*

Other names

Canonical SPDI

NC_000017.11:31229060: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.

Links

ClinGen: CA10603442 dbSNP: rs886041347 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	14115	14552

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.
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Dec 16, 2020	RCV000376782.39
Axillary freckling Cafe au lait spots, multiple Delayed fine motor development Inguinal freckling Large cafe-au-lait macules with irregular margins Lisch nodules	Pathogenic (1)	criteria provided, single submitter	Jan 1, 2017	RCV000626642.9
Neurofibromatosis, type 1	Pathogenic (9)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV000497042.32
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	Oct 31, 2018	RCV000762986.9
Cardiovascular phenotype Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Jan 27, 2022	RCV002311233.8
Juvenile myelomonocytic leukemia	Pathogenic (1)	criteria provided, single submitter	Feb 21, 2023	RCV003469215.1

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 (Jan 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Axillary freckling Delayed fine motor development Inguinal freckling Large cafe-au-lait macules with irregular margins Lisch nodules Cafe au lait spots, multiple Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000747344.1 First in ClinVar: May 12, 2018 Last updated: May 12, 2018
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: SCV000781952.1 First in ClinVar: Jul 07, 2018 Last updated: Jul 07, 2018
Pathogenic (Oct 31, 2018)	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: SCV000893431.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Jul 31, 2017)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000927362.1 First in ClinVar: Jul 24, 2019 Last updated: Jul 24, 2019 Comment: Patient analyzed with Noonan Syndrome Panel
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: SCV000588746.2 First in ClinVar: Aug 13, 2017 Last updated: Apr 18, 2020
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: SCV001479119.1 First in ClinVar: Feb 13, 2021 Last updated: Feb 13, 2021
Pathogenic (Dec 16, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329837.7 First in ClinVar: Dec 06, 2016 Last updated: Sep 21, 2018	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; Observed … (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; Observed in multiple patients with Neurofibromatosis type 1 referred for genetic testing at GeneDx and in published literature, including both apparent and confirmed de novo observations (Maynard 1997, Fahsold 2000, Jeong 2006, Ko 2013, Cali 2016, Pemov 2017, Cannon 2018, Tsipi 2018); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 25525159, 10712197, 30192422, 15146469, 32486389, 32408052, 9150739, 23668869, 9475595, 27838393, 16479075, 27498913, 25403449, 30014477, 19142971, 26969325, 18484666, 16773574, 29146900, 31730495, 29415745, 28068329, 30308447, 31766501, 31776437) (less)
Pathogenic (Apr 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 1 Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002061403.3 First in ClinVar: Jan 22, 2022 Last updated: Aug 05, 2023	Comment: PVS1, PS4, PM2
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: SCV002561770.1 First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022
Pathogenic (Jan 27, 2022)	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022) Method: clinical testing	Cardiovascular phenotype Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000581352.5 First in ClinVar: Jul 01, 2017 Last updated: Nov 29, 2022	Publications: PubMed (2) PubMed: 31776437‚ 34080803 Comment: The p.R816* variant (also known as c.2446C>T), located in coding exon 21 of the NF1 gene, results from a C to T substitution at nucleotide … (more) The p.R816* variant (also known as c.2446C>T), located in coding exon 21 of the NF1 gene, results from a C to T substitution at nucleotide position 2446. This changes the amino acid from an arginine to a stop codon within coding exon 21. This mutation has been reported multiple times in individuals with clinical features of neurofibromatosis type 1 (Maynard et al. Hum. Genet. 1997; 99:674-76; Bahuau et al. Am J Med Genet. 1998;75(3):265-72; Fahsold et al. Am. J. Hum. Genet. 2000; 66(3):790-818; Jeong et al. J. Korean Med. Sci. 2006;21(1):107-12; Bottillo et al. J. Pathol. 2009; 217(5):693-701; Stenman et al. Endocr. Pathol. 2015; 26(1):9-14; Kang E et al. J Hum Genet, 2020 Jan;65:79-89; N Abdel-Aziz N et al. Mol Genet Genomic Med, 2021 12;9:e1631). This mutation also segregated with disease in ten individuals from one family with neurofibromatosis (Bahuau et al. Am J Med Genet. 1998. 23;75(3):265-72). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 (May 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV004027791.1 First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023	Comment: Criteria applied: PVS1,PS3_MOD,PS4_MOD,PM2_SUP Clinical Features: Cafe au lait spots, multiple (present) , Mild short stature (present) Sex: female
Pathogenic (Feb 21, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Juvenile myelomonocytic leukemia Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004190764.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Dec 01, 2023)	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: SCV000628443.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (9) PubMed: 10712197‚ 23913538‚ 9150739‚ 9475595‚ 15146469‚ 18484666‚ 19142971‚ 23668869‚ 25403449 Comment: This sequence change creates a premature translational stop signal (p.Arg816) 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.Arg816) 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 NF1-related conditions (PMID: 9150739, 9475595, 10712197, 15146469, 18484666, 19142971, 23668869, 25403449). ClinVar contains an entry for this variant (Variation ID: 280055). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jul 01, 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: SCV005068228.1 First in ClinVar: Jul 07, 2024 Last updated: Jul 07, 2024
Pathogenic (Mar 01, 2019)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247188.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 2
Pathogenic (Feb 05, 2020)	no assertion criteria provided Method: clinical testing	Neurofibromatosis, type 1 Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001190818.1 First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020
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: SCV001739596.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
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: SCV001975048.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
click to load more click to collapse

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; Observed in multiple patients with Neurofibromatosis type 1 referred for genetic testing at GeneDx and in published literature, including both apparent and confirmed de novo observations (Maynard 1997, Fahsold 2000, Jeong 2006, Ko 2013, Cali 2016, Pemov 2017, Cannon 2018, Tsipi 2018); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 25525159, 10712197, 30192422, 15146469, 32486389, 32408052, 9150739, 23668869, 9475595, 27838393, 16479075, 27498913, 25403449, 30014477, 19142971, 26969325, 18484666, 16773574, 29146900, 31730495, 29415745, 28068329, 30308447, 31766501, 31776437)

Comment:

The p.R816* variant (also known as c.2446C>T), located in coding exon 21 of the NF1 gene, results from a C to T substitution at nucleotide position 2446. This changes the amino acid from an arginine to a stop codon within coding exon 21. This mutation has been reported multiple times in individuals with clinical features of neurofibromatosis type 1 (Maynard et al. Hum. Genet. 1997; 99:674-76; Bahuau et al. Am J Med Genet. 1998;75(3):265-72; Fahsold et al. Am. J. Hum. Genet. 2000; 66(3):790-818; Jeong et al. J. Korean Med. Sci. 2006;21(1):107-12; Bottillo et al. J. Pathol. 2009; 217(5):693-701; Stenman et al. Endocr. Pathol. 2015; 26(1):9-14; Kang E et al. J Hum Genet, 2020 Jan;65:79-89; N Abdel-Aziz N et al. Mol Genet Genomic Med, 2021 12;9:e1631). This mutation also segregated with disease in ten individuals from one family with neurofibromatosis (Bahuau et al. Am J Med Genet. 1998. 23;75(3):265-72). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Comment:

This sequence change creates a premature translational stop signal (p.Arg816*) 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 NF1-related conditions (PMID: 9150739, 9475595, 10712197, 15146469, 18484666, 19142971, 23668869, 25403449). ClinVar contains an entry for this variant (Variation ID: 280055). For these reasons, this variant has been 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutational spectrum of NF1 gene in 24 unrelated Egyptian families with neurofibromatosis type 1.	N Abdel-Aziz N	Molecular genetics & genomic medicine	2021	PMID: 34080803
Phenotype categorization of neurofibromatosis type I and correlation to NF1 mutation types.	Kang E	Journal of human genetics	2020	PMID: 31776437
Immunohistochemical NF1 analysis does not predict NF1 gene mutation status in pheochromocytoma.	Stenman A	Endocrine pathology	2015	PMID: 25403449
NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience.	Sabbagh A	Human mutation	2013	PMID: 23913538
Mutation spectrum of NF1 and clinical characteristics in 78 Korean patients with neurofibromatosis type 1.	Ko JM	Pediatric neurology	2013	PMID: 23668869
Germline and somatic NF1 mutations in sporadic and NF1-associated malignant peripheral nerve sheath tumours.	Bottillo I	The Journal of pathology	2009	PMID: 19142971
Germline and somatic NF1 gene mutations in plexiform neurofibromas.	Upadhyaya M	Human mutation	2008	PMID: 18484666
Novel and recurrent mutations in the NF1 gene in Italian patients with neurofibromatosis type 1.	De Luca A	Human mutation	2004	PMID: 15146469
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
Novel recurrent nonsense mutation causing neurofibromatosis type 1 (NF1) in a family segregating both NF1 and Noonan syndrome.	Bahuau M	American journal of medical genetics	1998	PMID: 9475595
Characterization and significance of nine novel mutations in exon 16 of the neurofibromatosis type 1 (NF1) gene.	Maynard J	Human genetics	1997	PMID: 9150739
click to load more click to collapse

Text-mined citations for rs886041347 ...

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 03, 2024

ClinVar Genomic variation as it relates to human health

NM_001042492.3(NF1):c.2446C>T (p.Arg816Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs886041347 ...