17-31338092-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001042492.3(NF1):c.6772C>T(p.Arg2258*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001042492.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461654Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727148
GnomAD4 genome
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:13
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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 for this gene and is associated with NF1-related disorders. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. A child can be more or less severly affected than a heterozygote parent (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 - Variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in multiple patients with NF1, including some cases with confirmed de novo inheritance (ClinVar, PMID: 10712197, 31776437). (SP) 1208 - Inheritance information for this variant is not currently available. (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000230389 / PMID: 10712197). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
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This sequence change creates a premature translational stop signal (p.Arg2237*) 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 neurofibromatosis type 1 (PMID: 10712197, 10862084, 12552569, 16479075, 23913538, 26962827). This variant is also known as R2258X. ClinVar contains an entry for this variant (Variation ID: 230389). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:7
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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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26962827, 10712197, 16479075, 25525159, 12112660, 27498913, 27617404, 12552569, 23913538, 10862084, 34308366, 31730495, 31717729, 31533797, 31370276, 32283115, 31776437) -
The NF1 c.6709C>T (p.Arg2237*) 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: 10712197 (2000), 10862084 (2000), 12552569 (2003), 23913538 (2013), 26962827 (2016), 31370276 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
The NF1 c.6772C>T; p.Arg2258Ter variant (rs876658541, ClinVar Variation ID: 230389), also known as c.6709C>T p.Arg2237Ter for NM_000267.3, is reported in the literature in multiple individuals affected with neurofibromatosis type 1 (De Luca 2003, Fahsold 2000, Jeong 2006, Messiaen 2000, Sabbagh 2013, Zhu 2016). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. 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 to be pathogenic. References: De Luca A et al. NF1 gene analysis based on DHPLC. Hum Mutat. 2003 Feb;21(2):171-2. PMID: 12552569 Fahsold R et al. 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. Am J Hum Genet. 2000 Mar;66(3):790-818. PMID: 10712197 Jeong SY et al. The spectrum of NF1 mutations in Korean patients with neurofibromatosis type 1. J Korean Med Sci. 2006 Feb;21(1):107-12. PMID: 16479075 Messiaen LM et al. Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Hum Mutat. 2000;15(6):541-55. PMID: 10862084 Sabbagh A et al. NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience. Hum Mutat. 2013 Nov;34(11):1510-8. PMID: 23913538 Zhu L et al. Clinical and Molecular Characterization of NF1 Patients: Single-Center Experience of 32 Patients From China. Medicine (Baltimore). 2016 Mar;95(10):e3043. PMID: 26962827 -
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NF1: PVS1, PS2, PM2, PS4:Moderate -
Neurofibromatosis, type 1;C4024216:Tibial pseudarthrosis Pathogenic:1
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NF1-related disorder Pathogenic:1
The NF1 c.6772C>T variant is predicted to result in premature protein termination (p.Arg2258*). This variant has been reported in individuals with neurofibromatosis type 1 (referred to as R2237X in Fahsold et al. 2000. PubMed ID: 10712197; Zhu et al. 2016. PubMed ID: 26962827). At PreventionGenetics, this variant has been identified in other affected patients. To our knowledge, this variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/230389/). Nonsense variants in NF1 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome Pathogenic:1
PM2_Supporting+PVS1+PM6_Supporting+PS4_Moderate+PP1_Strong+PP4 -
Café-au-lait macules with pulmonary stenosis Pathogenic:1
PVS1,PS2,PM2 -
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
The c.6709C>T (p.R2237*) alteration, located in exon 44 (coding exon 44) of the NF1 gene, consists of a C to T substitution at nucleotide position 6709. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 2237. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been described in multiple individuals meeting NIH diagnostic criteria for neurofibromatosis type 1 (NF1) (Fahsold, 2000; Xu, 2014; Zhu, 2016). This alteration is a recurring mutation due to its location in a CpG dinucleotide. Of note, this mutation is also designated as c.67772C>T and p.R2258* in published literature. Based on the available evidence, this alteration is classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
​Thep.R2258*pathogenic mutation (also known as c.6772C>T, p.R2237X, and c.6709C>T)<span style="font-size:12.7272720336914px">located in coding exon 45 of theNF1<span style="font-size:12.7272720336914px">gene, results from a C to T substitution at nucleotide position 6772. This changes the amino acid from an arginine to a stop codon within coding exon 45. This alteration was first described in three unrelated individuals who all met NIH diagnostic criteria forneurofibromatosis type 1 (NF1) (Fahsold R et al.Am J Hum Genet.2000;66(3):790-818). This alteration is a recurring mutation due to being located in a CpG dinucleotide. 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). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at