ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.4255A>C (p.Lys1419Gln) (rs199474790)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000059195 SCV000491218 likely pathogenic not provided 2016-12-05 criteria provided, single submitter clinical testing The K1419Q variant has been published previously in association with neurofibromatosis type 1 (NF1) (Upadhyaya et al., 1997). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. K1419Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. While functional studies in Drosophila have shown that K1419Q negatively impacts the function of the NF1 protein, no functional studies have been performed with human cells to our knowledge (Hannan et al., 2006). Missense variants in the same residue (K1419R) and in a nearby residue (K1423E/R/N) have been reported in the Human Gene Mutation Database in association with NF1 (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic.
UniProtKB/Swiss-Prot RCV000059195 SCV000090724 not provided not provided no assertion provided not provided

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