ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.5450C>G (p.Ser1817Cys) (rs368654378)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132225 SCV000187308 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
Invitae RCV000168027 SCV000218679 uncertain significance Neurofibromatosis, type 1 2018-12-31 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 1817 of the NF1 protein (p.Ser1817Cys). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs368654378, ExAC 0.01%). This variant has been reported in an individual with neurofibromatosis type 1 (PMID: 27322474). ClinVar contains an entry for this variant (Variation ID: 142804). 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: "Deleterious"; 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 RCV000484858 SCV000572284 uncertain significance not provided 2018-09-27 criteria provided, single submitter clinical testing This variant is denoted NF1 c.5450C>G at the cDNA level, p.Ser1817Cys (S1817C) at the protein level, and results in the change of a Serine to a Cysteine (TCT>TGT). This variant, also reported as p.Ser1838Cys using alternate nomenclature, was observed in at least one individual meeting the diagnostic criteria for Neurofibromatosis Type 1 (NF1) and has also been observed in an individual with liposarcoma (Ballinger 2016, Evans 2016). NF1 Ser1817Cys was observed at an allele frequency of 0.02% (23/126,618) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether NF1 Ser1817Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Fulgent Genetics,Fulgent Genetics RCV000515448 SCV000611412 uncertain significance Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis 2017-05-23 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000484858 SCV000806297 uncertain significance not provided 2017-05-09 criteria provided, single submitter clinical testing

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