ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.2991G>T (p.Arg997Ser) (rs755501749)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489444 SCV000577244 likely pathogenic not provided 2018-06-25 criteria provided, single submitter clinical testing The c.2991G>T variant in the NF1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.2991G>T variant is not observed in large population cohorts (Lek et al., 2016). In-silico splice models predict that c.2991G>T may damage the natural splice acceptor site in exon 23 and cause abnormal splicing. However, in the absence of RNA/functional studies, the actual effect of the c.2991G>T change in this individual is unknown. If c.2991G>T does not alter splicing, it will result in the R997S missense change. The R997S variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. This variant is within the GTPase activating protein domain (Luo et al., 2014). We interpret c.2991G>T as a likely pathogenic variant.
Invitae RCV000540077 SCV000628479 likely pathogenic Neurofibromatosis, type 1 2018-09-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 997 of the NF1 protein (p.Arg997Ser). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a NF1-related disease. This variant is de novo in an individual with NF1-related disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 426719). 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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