ClinVar Genomic variation as it relates to human health

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).

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.

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)

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.

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.

PVS1, PS4, PM2, PM6_Strong

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.

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.

PP4, PM2, PVS1

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.