Submissions for variant NM_001042492.3(NF1):c.3827G>A (p.Arg1276Gln)

gnomAD frequency: 0.00001  dbSNP: rs137854556

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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.
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
GeneDx	RCV000059193	SCV000568609	pathogenic	not provided	2022-03-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: R1276Q reduces or abolishes Ras activity in vitro (Thomas et al., 2012; Wallis et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32107864, 24951259, 16479075, 27135912, 12522551, 23906300, 22807134, 23047742, 24803665, 22155606, 17311297, 15060124, 21142935, 27322474, 10712197, 27838393, 26607044, 29522274, 29804243, 31595648, 19221814, 23668869, 15863657, 23758643, 31776437, 25486365)
Invitae	RCV000213660	SCV000753645	pathogenic	Neurofibromatosis, type 1	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1276 of the NF1 protein (p.Arg1276Gln). This variant is present in population databases (rs137854556, gnomAD 0.004%). This missense change has been observed in individuals with neurofibromatosis type 1 (PMID: 10712197, 15060124, 16479075, 19221814, 23668869, 27322474). ClinVar contains an entry for this variant (Variation ID: 68341). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NF1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects NF1 function (PMID: 9109662, 22807134). This variant disrupts the p.Arg1276 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9668168, 10712197, 26635368). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000213660	SCV000782001	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
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.
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
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	2021-11-22	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.
Medical Genomics Laboratory, Department of Genetics UAB	RCV000213660	SCV000999183	pathogenic	Neurofibromatosis, type 1	2019-06-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002318951	SCV001182825	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-12-20	criteria provided, single submitter	clinical testing	The p.R1276Q variant (also known as c.3827G>A), located in coding exon 28 of the NF1 gene, results from a G to A substitution at nucleotide position 3827. The arginine at codon 1276 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in multiple individuals fulfilling diagnostic criteria for neurofibromatosis type 1 (NF1) (Mattocks C et al. J. Med. Genet. 2004 Apr;41:e48; Wimmer K et al. Hum. Mutat. 2007 Jun;28:599-612; Ko JM et al. Pediatr. Neurol. 2013 Jun;48:447-53; Evans DG et al. EBioMedicine 2016 May;7:212-20). This alteration has been shown to impair protein function (Wallis D et al. Hum. Mutat., 2018 06;39:816-821). In addition, this alteration is located in the arginine finger of the GAP-related domain (GRD), which is an essential catalytic element for RasGAP activity (Ambry internal data; Scheffzek K et al. Science, 1997 Jul;277:333-8; Scheffzek K et al. EMBO J., 1998 Aug;17:4313-27; Fahsold R et al. Am. J. Hum. Genet. 2000 Mar;66:790-818; Kiel C et al. Mol. Syst. Biol. 2014 May;10:727). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this variant is classified as a pathogenic mutation.
CeGaT Center for Human Genetics Tuebingen	RCV000059193	SCV001249044	pathogenic	not provided	2019-11-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000213660	SCV001479017	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000059193	SCV002018313	pathogenic	not provided	2020-11-18	criteria provided, single submitter	clinical testing
3billion	RCV000213660	SCV002058250	pathogenic	Neurofibromatosis, type 1	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068341, PS1_S). The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 10712197, 15060124, 16479075, PS4_S). Different missense changes at the same codon have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000353,VCV000068340,VCV000694608, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.887, 3CNET: 0.976, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Institute of Human Genetics, University Hospital Muenster	RCV000213660	SCV002499677	pathogenic	Neurofibromatosis, type 1	2022-03-03	criteria provided, single submitter	clinical testing	ACMG categories: PS3,PM2,PM7,PP3,PP4,PP5
Genome-Nilou Lab	RCV000213660	SCV002559997	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470752	SCV002768553	pathogenic	Neurofibromatosis-Noonan syndrome	2020-07-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine (exon 28). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (GAP, GTPase Activating Domain; PMID: 31595648). (N) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Four different variants in the same codon, resulting in changes to glycine, proline, leucine and glutamic acid, have also been shown to cause neurofibromatosis (PMID: 31595648; ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This is a recurrent variant that has been previously reported as pathogenic in multiple patients with neurofibromatosis (ClinVar). Reports also suggest that this variant and other changes affecting the same residue are also associated to a distinct phenotype with Noonan-like features (PMID: 31595648). (P) 1206 - Variant is paternally inherited. However, a child can be more or less severly affected than carrier parent due to variable expressivity (PMID: 20301288). (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Mayo Clinic Laboratories, Mayo Clinic	RCV000059193	SCV004227872	pathogenic	not provided	2022-05-10	criteria provided, single submitter	clinical testing	PP4, PM1, PM2, PS3, PS4_moderate
UniProtKB/Swiss-Prot	RCV000059193	SCV000090722	not provided	not provided		no assertion provided	not provided
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.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000059193	SCV001959873	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000059193	SCV001965844	pathogenic	not provided		no assertion criteria provided	clinical testing