ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.5248A>G (p.Lys1750Glu) (rs1131691103)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492200 SCV000581303 likely pathogenic Hereditary cancer-predisposing syndrome 2016-02-06 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000632446 SCV000753627 uncertain significance Neurofibromatosis, type 1 2018-08-30 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 1750 of the NF1 protein (p.Lys1750Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported as de novo in an individual affected with with neurofibromatosis I in the Leiden Open-source Variation Database (PMID: 21520333), though phenotypic details and parental data are not provided. ClinVar contains an entry for this variant (Variation ID: 428982). 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: "Benign"; 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 RCV000680829 SCV000808277 likely pathogenic not provided 2018-03-18 criteria provided, single submitter clinical testing The K1750E variant has been reported previously in the Leiden Open Variant Database and the Human Gene Mutation Database as a de novo variant; however, the variant is not found in the referenced publication and was obtained by personal communication (Fokkema et al., 2011; Stenson et al., 2014; vanMinkelen et al., 2014). The variant is not observed in large population cohorts (Lek et al., 2016). K1750E 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

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