ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.3827G>A (p.Arg1276Gln) (rs137854556)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000059193 SCV000884243 pathogenic not provided 2017-08-29 criteria provided, single submitter clinical testing The NF1 c.3827G>A, p.Arg1276Gln variant (rs137854556) is a recurrent alteration in individuals diagnosed with neurofibromatosis type I (Ben-Shachar 2013, Fahsold 2000, Jeong 2006, Mattocks 2004, Nemethova 2013, LOVD NF1 database). Functional characterization of the variant protein indicates a significant impairment in activating the catalysis of GTP bound to RAS proteins, resulting in an elevated level of activated RAS kinase (Ahmadian 1997, Thomas 2012). Other missense variants at this position, p.Arg1276Gly and p.Arg1276Pro, have also been implicated in neurofibromatosis type I (Fahsold 2000, Mattocks 2004). The p.Arg1276Gln variant is listed as pathogenic in ClinVar (Variation ID: 68341), and is observed once in the Genome Aggregation Database general population database (1/245936 alleles). The arginine at residue 1276 is highly conserved, and is the catalytic residue for the GAP-related domain of NF1. Computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the missense variant has an impact on the protein structure or function, consistent with the functional studies. Based on the above information, the p.Arg1276Gln variant is classified as pathogenic. References: LOVD NF1 database: https://grenada.lumc.nl/LOVD2/mendelian_genes/home.php?select_db=NF1 Ahmadian M et al. Confirmation of the arginine-finger hypothesis for the GAP-stimulated GTP-hydrolysis reaction of Ras. Nat Struct Biol. 1997; 4(9):686-9. Ben-Shachar S et al. Increased rate of missense/in-frame mutations in individuals with NF1-related pulmonary stenosis: a novel genotype-phenotype correlation. Eur J Hum Genet. 2013; 21(5):535-9. 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; 66(3):790-818. Jeong S et al. The spectrum of NF1 mutations in Korean patients with neurofibromatosis type 1. J Korean Med Sci. 2006; 21(1):107-12. Mattocks C et al. Automated comparative sequence analysis identifies mutations in 89 percent of NF1 patients and confirms a mutation cluster in exons 11-17 distinct from the GAP related domain. J Med Genet. 2004; 41(4):e48. Nemethova M et al. Thirty-nine novel neurofibromatosis 1 (NF1) gene mutations identified in Slovak patients. Ann Hum Genet. 2013; 77(5):364-79. Thomas L et al. Assessment of the potential pathogenicity of missense mutations identified in the GTPase-activating protein (GAP)-related domain of the neurofibromatosis type-1 (NF1) gene. Hum Mutat. 2012; 33(12):1687-96.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000762988 SCV000898848 pathogenic Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis 2018-01-22 criteria provided, single submitter clinical testing NF1 NM_000267.3 exon 28 p.Arg1276Gln (c.3827G>A): This variant has been reported in the literature in at least 8 individuals (Fahsold 2000 PMID:10712197, Mattocks 2004 PMID:15060124, Jeong 2006 PMID:16479075, Ko 2013 PMID:23668869, Nemethova 2013 PMID:23758643, Evans 2016 PMID:27322474). This variant was reported to segregate with disease in at least 2 affected family members (Ko 2013 PMID:23668869, Nemethova 2013 PMID:23758643). This variant was also reported in at least 2 individuals with Watson syndrome (Ben-Shachar 2013 PMID:23047742, Evans 2016 PMID:27322474). This variant is present in 1/15300 African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs137854556). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:68341). Evolutionary conservation and computational predictive tools also suggest that this variant may impact the protein. In addition, functional studies have suggested a disease causing impact of this variant, with increased levels of GTP-bound Ras protein vs. wild type (Thomas 2012 PMID:22807134). Of note, two other variants at this codon (p.Arg1276Gly and p.Arg1276Pro) have been reported in association with disease, supporting that this region has functional significance. In summary, this variant is classified as pathogenic based on the data above.
Center for Human Genetics, Inc RCV000213660 SCV000782001 pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000059193 SCV000511540 pathogenic not provided 2016-06-22 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762988 SCV000893433 pathogenic Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000059193 SCV000568609 pathogenic not provided 2018-08-31 criteria provided, single submitter clinical testing The R1276Q variant has been reported previously in association with neurofibromatosis type 1 (Ko et al., 2013; Nemethova et al., 2013; Evans et al., 2016). The R1276Q variant is observed in 1/15300 (0.0065%) alleles from individuals of African background in large population cohorts (Lek et al., 2016). The variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position within the Ras-Gap domain that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, functional studies done in vitro demonstrate R1276Q reduces the levels of Ras activity and elevates RasGTP levels compared to controls (Thomas et al., 2012). In summary, we consider this variant to be pathogenic.
GenomeConnect, ClinGen RCV000213660 SCV000607043 not provided Neurofibromatosis, type 1 no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Invitae RCV000213660 SCV000753645 pathogenic Neurofibromatosis, type 1 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1276 of the NF1 protein (p.Arg1276Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with neurofibromatosis type 1 (PMID: 10712197, 15060124, 16479075, 19221814, 23668869 27322474). ClinVar contains an entry for this variant (Variation ID: 68341). A different missense substitution at this codon (p.Arg1276Pro) has been determined to be pathogenic (PMID: 9668168, 10712197, 26635368). This suggests that the arginine residue is critical for NF1 protein function and that other missense substitutions at this position may also be pathogenic. This sequence change falls within a mutational hotspot region. Arg1276 is known to be a critical catalytic residue in the GAP related domain of NF1, which has been found to interact with Ras and GTP, and is thought to prevent uncontrolled cell proliferation by modulating Ras activity (PMID: 9302992). Experimental studies have shown that this missense change leads to significantly elevated levels of activated GTP-bound Ras (PMID: 22807134) and that it compromises GAP-stimulated GTP hydrolysis (PMID: 9109662), indicating that the Arg1276Gln change impairs NF1 protein function. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000824729 SCV000271423 pathogenic Neurofibromatosis, type 1; Café-au-lait macules with pulmonary stenosis 2016-01-29 criteria provided, single submitter clinical testing The p.Arg1276Gln variant in NF1 has been reported in >15 individuals with Neurof ibromatosis type 1 (NF1) (Fahsold 2000, Mattocks 2004, Jeong 2006, Thomas 2012, Nemethova 2013, Mendelian Genes LOVD), 1 individual with Watson syndrome (Ben-sh achar 2013), and segregated with disease in 2 affected relatives from 2 families (Nemethova 2013, Mendelian Genes LOVD). This variant was also reported to have occurred de novo in three of these individuals (Mendelian Genes LOVD). It was al so absent from large population studies (dbSNP rs137854556). In-vitro functional studies provide some evidence that this variant severely impacts protein functi on (Ahmadian 1997, Thomas 2012). In summary, this variant meets criteria to be c lassified as pathogenic for Neurofibromatosis 1 in an autosomal dominant manner based upon segregation studies, absence from controls, and functional evidence.
UniProtKB/Swiss-Prot RCV000059193 SCV000090722 not provided not provided no assertion provided not provided

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