ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.4172G>C (p.Arg1391Thr) (rs1555618516)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626643 SCV000747345 likely pathogenic Multiple cafe-au-lait spots; Abnormality of vision; Neurofibromas 2017-01-01 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000660052 SCV000782012 uncertain significance Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
Invitae RCV000660052 SCV000962246 pathogenic Neurofibromatosis, type 1 2020-01-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with threonine at codon 1391 of the NF1 protein (p.Arg1391Thr). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with or suspected of having neurofibormatosis type 1 (NF1) (PMID: 27322474, 24789688) and also been observed de novo in an individual with clinical features of the NF1- Noonan syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 523345). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg1391 amino acid residue in NF1. Other variant(s) that disrupt this residue have been observed in individuals with NF1-related conditions (PMID:9003501, 27322474, 9003501, 22807134, 7581973, 16513807), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001021989 SCV001183675 pathogenic Hereditary cancer-predisposing syndrome 2019-04-17 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes);Structural Evidence;Well-characterized mutation at same position

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