ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.5546G>A (p.Arg1849Gln) (rs786202112)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164762 SCV000215438 pathogenic Hereditary cancer-predisposing syndrome 2015-07-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Last nucleotide of exon,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Functionally-validated splicing mutation
Invitae RCV000408787 SCV000542194 pathogenic Neurofibromatosis, type 1 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1849 of the NF1 protein (p.Arg1849Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant also falls at the last nucleotide of exon 37 of the NF1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many individuals and families affected with neurofibromatosis 1 (NF1) (PMID: 25325900, 10607834, 23668869, 11857752, 10980545, 18484666, 18546366, 24932921, 10862084, 12807981, 10712197, 23913538). ClinVar contains an entry for this variant (Variation ID: 185354). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this missense change, as it falls at the last nucleotide of an exon, affects the donor splice site and results in skipping of the following exon, leading to a premature stop codon and a truncated NF1 protein (PMID: 10607834, 10980545). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000494213 SCV000583307 pathogenic not provided 2018-06-15 criteria provided, single submitter clinical testing The R1849Q variant has been reported previously in association with neurofibromatosis type 1 (Ars et al., 2000; Paria et al., 2014; Evans et al., 2016). It is reported as pathogenic in ClinVar by other clinical laboratories, but additional evidence is not available (ClinVar SCV000215438.2, SCV000542194.1; Landrum et al., 2015). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). R1849Q 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 that is conserved across species, and in silico analysis predicts this variant damages the natural splice donor site for exon 37. Additionally, RNA studies have shown that R1849Q results in the skipping of exon 37 and the creation of a frameshift with a premature stop codon in exon 38, referred to as exons 29 and 30 in this publication due to alternate nomenclature (Girodon-Boulandet et al., 2000). In summary, we consider this variant to be pathogenic.
Center for Human Genetics, Inc RCV000408787 SCV000782055 pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762993 SCV000893438 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
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000408787 SCV000484938 pathogenic Neurofibromatosis, type 1 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.