ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.7847G>A (p.Arg2616Gln) (rs560262404)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129502 SCV000184274 uncertain significance Hereditary cancer-predisposing syndrome 2015-11-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Co-occurence with mutation in same gene (phase unknown)
Invitae RCV000679416 SCV000554962 likely benign not provided 2019-03-04 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000458322 SCV000679830 uncertain significance Neurofibromatosis, type 1 2017-08-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679416 SCV000806322 uncertain significance not provided 2017-12-11 criteria provided, single submitter clinical testing
GeneDx RCV000679416 SCV000808670 uncertain significance not provided 2018-04-18 criteria provided, single submitter clinical testing This variant is denoted NF1 c.7847G>A at the cDNA level, p.Arg2616Gln (R2616Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant was observed in a family with a clinical diagnosis of neurofibromatosis type 1; however, a pathogenic nonsense variant in NF1 was found to segregate with disease in this family (Messiaen 2000). This variant was also observed in two siblings with Asperger syndrome (Toma 2014). NF1 Arg2616Gln was observed at an allele frequency of 0.007% (8/111,574) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the C-terminal domain (Luo 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether NF1 Arg2616Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000679416 SCV000884247 likely benign not provided 2017-06-16 criteria provided, single submitter clinical testing The NF1 c.7910G>A; p.Arg2637Gln variant (rs560262404), also known as c.7847G>A; p.Arg2616Gln, has been reported in the literature in a patient who carries a pathogenic NF1 variant in trans, and did not segregate with disease in this family (Messiaen 2000). This variant is reported in ClinVar (Variation ID: 141130), and is observed in general population databases at frequencies of 0.02 percent (1/5008 alleles, 1000 Genome Project), and 0.007 percent (8/111574 alleles, Genome Aggregation Database). The arginine at codon 2637 is highly conserved, but computational algorithms do not agree as to the effect this variant may have on the protein (SIFT: Tolerated, PolyPhen2: Probably Damaging, MutationTaster: Disease Causing, Align GVGD: C0). Taken together, this variant is considered likely benign. REFERENCES Link to ClinVar database for p.Arg2637Gln: https://www.ncbi.nlm.nih.gov/clinvar/variation/141130/ 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.

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