ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.4276C>G (p.Gln1426Glu)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000792034 SCV000931306 likely pathogenic Neurofibromatosis, type 1 2018-09-27 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 1426 of the NF1 protein (p.Gln1426Glu). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual with clinical features of neurofibromatosis type 1 (Invitae). Also, it has been reported in the literature in an individual affected with neurofibromatosis type 1 (PMID: 23913538). 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. Variants that disrupt the p.Gln1426 amino acid residue in NF1 have been observed in affected individuals (PMID: 23047742,8437860, 17114577). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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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