ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.910C>T (p.Arg304Ter) (rs786203950)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167474 SCV000218330 pathogenic Hereditary cancer-predisposing syndrome 2014-12-26 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000468520 SCV000542003 pathogenic Neurofibromatosis, type 1 2019-11-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 304 (p.Arg304*) of the NF1 gene. This variant is not present in population databases (rs786203950, ExAC no frequency). This variant has been reported in the literature in individuals affected with neurofibromatosis, type 1 (PMID: 23668869, 16786508, 23913538, 10862084). ClinVar contains an entry for this variant (Variation ID: 187722). Experimental studies have shown that instead of creating a truncated protein, this variant causes skipping of exon 9 (also known as exon 7 in the literature). This creates a smaller transcript which lacks these codons and is expressed at a decreased amount when compared to wild-type transcript (PMID: 9463322, 10874316). For these reasons, this variant has been classified as Pathogenic.
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000468520 SCV000590893 pathogenic Neurofibromatosis, type 1 2017-06-06 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000508304 SCV000604459 pathogenic not specified 2018-08-15 criteria provided, single submitter clinical testing The NF1 c.910C>T; p.Arg304Ter variant (rs786203950) has been described in several individuals with neurofibromatosis type 1 (NF1) (see link below, Ko 2013, Upadhyaya 2008). It is reported as pathogenic in ClinVar (Variation ID: 187722) and observed on only 1 allele in the Genome Aggregation Database. 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 pathogenic. References: Link to NF1 LOVD Database for p.Arg304Ter: https://grenada.lumc.nl/LOVD2/mendelian_genes/variants.php?select_db=NF1&action=search_all&search_Variant%2FDNA=c.910C%3ET Ko JM et al. (2013) Mutation spectrum of NF1 and clinical characteristics in 78 Korean patients with neurofibromatosis type 1. Pediatr Neurol. 48(6):447-53. Upadhyaya M et al. (2008) Germline and somatic NF1 gene mutations in plexiform neurofibromas. Hum Mutat. 29(8):E103-11.
GeneDx RCV000579282 SCV000680718 pathogenic not provided 2018-06-21 criteria provided, single submitter clinical testing The R304X nonsense variant in the NF1 gene has been reported previously in several individuals with neurofibromatosis type 1 with a range of severity (e.g., Fahsold et al 2000; Hoffmeyer et al., 1998; Messiaen et al., 2000, Wimmer et al., 2000). This pathogenic variant is predicted to cause loss of normal protein function and expression. Several in vitro studies demonstrated that R304X may result in skipping of exon 9 (also reported as exon 7) in some but not all cells, thus creating a shortened protein (including Messiaen et al., 2000; Wimmer et al., 2000; Bottillo et al., 2007; Hernandez-Imaz et al., 2015). Additionally, R304X has been observed in 1/111662 (0.0004%) alleles from individuals of European (Non-Finnish) background in large population cohorts (Lek et al., 2016). Based on all available evidence, we consider R304X to be pathogenic.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000468520 SCV000781883 pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
Medical Genetics, University of Parma RCV000468520 SCV001218910 pathogenic Neurofibromatosis, type 1 2019-12-20 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197945 SCV001368730 pathogenic Cafe-au-lait spot; Renal insufficiency; Renal cyst; Osteoporosis; Neurofibromas; Breast carcinoma 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2. This variant was detected in heterozygous state.

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