ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.4168C>T (p.Leu1390Phe) (rs199474789)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195735 SCV000253693 pathogenic Neurofibromatosis, type 1 2020-02-26 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 1390 of the NF1 protein (p.Leu1390Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with disease in a large family affected with neurofibromatosis-Noonan syndrome (NFNS) (PMID: 19845691). This missense change was observed in 7 affected individuals and absent in 11 unaffected individuals within this family. It has also been seen in several individuals with features of neurofibromatosis type 1 (Invitae). ClinVar contains an entry for this variant (Variation ID: 30992). 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: Probably Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000059194 SCV000491217 likely pathogenic not provided 2016-11-29 criteria provided, single submitter clinical testing The L1390F variant has been observed previously in one family with neurofibromatosis-Noonan syndrome (NFNS) (Nyström et al., 2009). 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. L1390F is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position within the Ras-GAP domain that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (L1390P) and in nearby residues (R1391G/S, P1395H) have been reported in the Human Gene Mutation Database in association with NF1-associated disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000195735 SCV000863575 pathogenic Neurofibromatosis, type 1 2018-12-20 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV000195735 SCV001478945 likely pathogenic Neurofibromatosis, type 1 2020-10-26 criteria provided, single submitter clinical testing
OMIM RCV000023983 SCV000045274 pathogenic Neurofibromatosis-Noonan syndrome 2009-12-01 no assertion criteria provided literature only
UniProtKB/Swiss-Prot RCV000059194 SCV000090723 not provided not provided no assertion provided not provided

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