ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.3461A>T (p.Asn1154Ile) (rs371544233)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493463 SCV000583011 likely pathogenic not provided 2018-03-29 criteria provided, single submitter clinical testing The N1154I variant in the NF1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. N1154I is reported as a likely pathogenic variant in ClinVar by a different clinical laboratory and apparently occurred de novo in a patient with neurofibromatosis type 1 (ClinVar SCV000542232.2; Landrum et al., 2015). A missense variant in the same codon, N1154T, has been reported in one proband with a clinical diagnosis of neurofibromatosis type 1 (Pasmant et al., 2015). The N1154I variant is not observed in large population cohorts (Lek et al., 2016). The N1154I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This variant is located in GTPase activating protein domain (Luo et al., 2014; Xu et al., 1990; Thomas et al., 2012). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, we consider N1154I to be a likely pathogenic variant.
Invitae RCV000467969 SCV000542232 likely pathogenic Neurofibromatosis, type 1 2017-02-27 criteria provided, single submitter clinical testing This sequence change replaces asparagine with isoleucine at codon 1154 of the NF1 protein (p.Asn1154Ile). The asparagine residue is moderately conserved and there is a large physicochemical difference between asparagine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with neurofibromatosis type 1 (NF1) (PMID: 23656349). In another case, family studies have indicated that this variant was not present in the parents of an individual with NF1, which suggests that it was de novo in that affected individual (Invitae). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change that has been reported to be de novo in individuals affected with NF1. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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