ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.1166A>G (p.His389Arg) (rs149739570)

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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 RCV000130738 SCV000185629 uncertain significance Inborn genetic diseases 2014-06-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Fulgent Genetics,Fulgent Genetics RCV000765345 SCV000896609 uncertain significance Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000680982 SCV000808431 uncertain significance not provided 2018-01-22 criteria provided, single submitter clinical testing This variant is denoted NF1 c.1166A>G at the cDNA level, p.His389Arg (H389R) at the protein level, and results in the change of a Histidine to an Arginine (CAC>CGC). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported in a myeloproliferative neoplasm (Casolari 2017). NF1 His389Arg was observed at an allele frequency of 0.02% (20/126628 alleles) in individuals of European (non-Finnish) 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 His389Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000708723 SCV000822090 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000204985 SCV000259876 uncertain significance Neurofibromatosis, type 1 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 389 of the NF1 protein (p.His389Arg). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs149739570, ExAC 0.01%). This variant has been observed in an individual affected with midaortic syndrome (PMID:  29483232). ClinVar contains an entry for this variant (Variation ID: 141982). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Yale Center for Mendelian Genomics,Yale University RCV000845190 SCV000987126 likely pathogenic Midaortic syndrome 2018-02-26 no assertion criteria provided literature only

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