ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.4098C>G (p.His1366Gln) (rs1555617377)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000632493 SCV000753678 uncertain significance Neurofibromatosis, type 1 2019-12-02 criteria provided, single submitter clinical testing This sequence change replaces histidine with glutamine at codon 1366 of the NF1 protein (p.His1366Gln). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NF1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000681301 SCV000808763 uncertain significance not provided 2018-05-18 criteria provided, single submitter clinical testing This variant is denoted NF1 c.4098C>G at the cDNA level, p.His1366Gln (H1366Q) at the protein level, and results in the change of a Histidine to a Glutamine (CAC>CAG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. NF1 His1366Gln was not observed in large population cohorts (Lek 2016). This variant is located in the GTPase activating protein domain (Thomas 2012, 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 His1366Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV001021852 SCV001183520 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-01 criteria provided, single submitter clinical testing Insufficient evidence

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