ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.4369A>C (p.Lys1457Gln)

dbSNP: rs878853893
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000699721 SCV000828444 pathogenic Neurofibromatosis, type 1 2024-04-22 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1436 of the NF1 protein (p.Lys1436Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis type 1 (PMID: 21520333, 22807134, 24789688; Invitae). ClinVar contains an entry for this variant (Variation ID: 577061). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NF1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects NF1 function (PMID: 22807134). This variant disrupts the p.Lys1436 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21354044, 23913538, 24789688; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001766524 SCV002008453 pathogenic not provided 2021-10-18 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: significantly elevated GTP-bound RAS in comparison to wild-type (Thomas 2012); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22807134, 28529006, 24789688, 25486365)

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