ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.3604G>T (p.Ala1202Ser) (rs146641724)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130378 SCV000185232 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-20 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (benign)
Invitae RCV000206873 SCV000259575 uncertain significance Neurofibromatosis, type 1 2019-12-03 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 1202 of the NF1 protein (p.Ala1202Ser). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and serine. This variant is not present in population databases (rs146641724, ExAC no frequency). This variant has been observed in an individual affected with neurofibromatosis type 1 (NF1) (PMID: 26635368), and in an individual with clinical suspicion of NF1 (PMID: 16944272). ClinVar contains an entry for this variant (Variation ID: 141747). In vitro experimental studies performed in yeast have shown that this missense change does not alter NF1 protein binding to SPRED1 (PMID: 26635368). 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 RCV000680625 SCV000808068 uncertain significance not provided 2018-03-08 criteria provided, single submitter clinical testing This variant is denoted NF1 c.3604G>T at the cDNA level, p.Ala1202Ser (A1202S) at the protein level, and results in the change of an Alanine to a Serine (GCT>TCT). This variant has been reported in an individual suspected of having neurofibromatosis type 1 (NF1) syndrome while functional work has suggested this variant does not impact the protein's ability to bind to SPRED1 (Griffiths 2007, Hirata 2016). NF1 Ala1202Ser was observed at an allele frequency of 0.02% (2/8,732) in individuals of African ancestry 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether NF1 Ala1202Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Fulgent Genetics,Fulgent Genetics RCV000764108 SCV000895076 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

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