17-31226459-AC-ACC

Variant names:

• chr17-31226459-A-AC
• rs587781807
• NM_001042492.3:c.2033dupC

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001042492.3(NF1):​c.2033dupC​(p.Ile679AspfsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P678P) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000019 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NF1 NM_001042492.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:27 O:1
• Conservation: PhyloP100: 3.31

Genes affected

NF1 (HGNC:7765): (neurofibromin 1) This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-31226459-A-AC is Pathogenic according to our data. Variant chr17-31226459-A-AC is described in ClinVar as [Pathogenic]. Clinvar id is 141513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.2033dupC	p.Ile679AspfsTer21	frameshift_variant	Exon 18 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.2033dupC	p.Ile679AspfsTer21	frameshift_variant	Exon 18 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.2033dupC	p.Ile679AspfsTer21	frameshift_variant	Exon 18 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 4 AN: 151556 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000192 AC: 28 AN: 1461398 Hom.: 0 Cov.: 34 AF XY: 0.0000165 AC XY: 12 AN XY: 727018

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000264 AC: 4 AN: 151674 Hom.: 0 Cov.: 31 AF XY: 0.0000270 AC XY: 2 AN XY: 74140

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:27 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:10

Dec 15, 2020

Department of Pediatrics, Memorial Sloan Kettering Cancer Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 03, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NF1 c.2033dupC (p.Ile679AspfsX21) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. germline c.2033dupC has been reported in the literature in individuals affected with Neurofibromatosis Type 1 (example,Tsipi_2018). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. This variant has also been observed as a somatic change in myeloproliferative disorders(MPDs). The following publications have been ascertained in the context of this evaluation (PMID: 30308447, 27069254, 10678181, 23460398, 29872168, NCCN_MDS). ClinVar contains an entry for this variant (Variation ID: 141513). Based on the evidence outlined above, the variant was classified as pathogenic. -

Aug 24, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 26, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2022

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ile679fs variant in NF1 has been reported in at least 16 individuals with Neurofibromatosis type 1 (Heim 1995 PMID: 7655472, Wimmer 2007 PMID: 17311297, Pros 2008 PMID: 18546366, Valero 2011 PMID: 21354044). This variant has also been reported in ClinVar (Variation ID# 141513). This variant has been identified in 2/10234 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs587781807). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 679 and leads to a premature termination codon 21 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the NF1 gene is an established disease mechanism in neurofibromatosis type 1. In summary, this variant meets criteria to be classified as pathogenic for neurofibromatosis type 1 in an autosomal dominant manner. ACMG/AMP criteria applied: PVS1, PS4. -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1+PM2_Supporting+PM6+PS4_Moderate+PP4 -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ile679Aspfs*21) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with neurofibromatosis type 1 (PMID: 7655472, 17311297, 18546366, 21354044, 23656349, 23668869). This variant is also known as 2027insC and c.2033_2034insC. ClinVar contains an entry for this variant (Variation ID: 141513). For these reasons, this variant has been classified as Pathogenic. -

Dec 20, 2019

Medical Genetics, University of Parma

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:10

Sep 29, 2015

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshift variant causes the premature termination of NF1 protein synthesis. In addition, it has been reported in individuals and families affected with neurofibromatosis 1 in the published literature (PMID: 7655472 (1995), 10712197 (2000), 21354044 (2011), 23668869 (2013), 30308447 (2018)). Therefore, the variant is classified as pathogenic. -

Aug 31, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4, PM2, PVS1 -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NF1: PVS1, PS4:Moderate -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 15, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 29, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 7655472, 34418705, 32980694, 28152038, 29922827, 34427956, 17311297, 23656349, 25074460, 18546366, 21354044, 30308447, 30877234, 10712197, 31730495, 31533797, 34308366, 32107864, 31370276, 32338768, 33332384, 31776437) -

Jul 27, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.2033dupC; p.Ile679AspfsTer21 variant (rs587781807), is reported in the literature in multiple individuals affected with neurofibromatosis type I (NF1; Duat 2015, Ko 2013, LaDuca 2017, Pros 2008, Valero 2011, van Minkelen 2014, Wimmer 2007). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 141513), and is also absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Duat Rodríguez A et al. Phenotypic and genetic features in neurofibromatosis type 1 in children. An Pediatr (Barc). 2015 Sep;83(3):173-82. Ko JM et al. Mutation spectrum of NF1 and clinical characteristics in 78 Korean patients with neurofibromatosis type 1. Pediatr Neurol. 2013 Jun;48(6):447-53. LaDuca H et al. Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels. PLoS One. 2017 Feb 2;12(2):e0170843. Pros E et al. Nature and mRNA effect of 282 different NF1 point mutations: focus on splicing alterations. Hum Mutat. 2008 Sep;29(9):E173-93. Valero MC et al. A highly sensitive genetic protocol to detect NF1 mutations. J Mol Diagn. 2011 Mar;13(2):113-22. van Minkelen R et al. A clinical and genetic overview of 18?years neurofibromatosis type 1 molecular diagnostics in the Netherlands. Clin Genet. 2014 Apr;85(4):318-27. Wimmer K et al. Extensive in silico analysis of NF1 splicing defects uncovers determinants for splicing outcome upon 5' splice-site disruption. Hum Mutat. 2007 Jun;28(6):599-612. -

NF1-related disorder Pathogenic:2

Feb 26, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS4, PM2, PM6_Strong -

Dec 11, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NF1 c.2033dupC variant is predicted to result in a frameshift and premature protein termination (p.Ile679Aspfs*21). This variant has been documented as causative for neurofibromatosis type 1 (NF1) in several patients (Heim et al. 1995. PubMed ID: 7655472; Rodríguez et al. 2015. PubMed ID: 25541118; Tsipi et al. 2018. PubMed ID: 30308447) including one patient with NF1 and juvenile myelomonocytic leukemia (JMML) (van Minkelen et al. 2014. PubMed ID: 23656349, see additional association with JMML in Sakaguchi et al. 2013. PubMed ID: 23832011; van Minkelen et al. 2014. PubMed ID: 23656349). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141513/). Frameshift variants in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Neurofibromatosis, type 1;C4024216:Tibial pseudarthrosis Pathogenic:1

Nov 10, 2018

The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Gastric cancer Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Juvenile myelomonocytic leukemia Pathogenic:1

Feb 29, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 11, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2033dupC pathogenic mutation (also known as 2027insC and 2033insC), located in coding exon 18 of the NF1 gene, results from a duplication of C at nucleotide position 2033, causing a translational frameshift with a predicted alternate stop codon. This mutation has been reported in mutliple NF1 patients (Heim RA et al. Hum. Mol. Genet. 1995; 4:975-81; Fahsold R et al. Am. J. Hum. Genet. 2000; 66:790-818). In addition to the clinical data presented in the literature, since frameshifts 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). -

Chromosome 17q11.2 deletion syndrome, 1.4Mb Pathogenic:1

Sep 14, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587781807; hg19: chr17-29553477;