ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.4337T>C (p.Leu1446Pro)

dbSNP: rs199474733
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001379175 SCV001576926 pathogenic Neurofibromatosis, type 1 2024-08-07 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1425 of the NF1 protein (p.Leu1425Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 10220149, 10607834, 10712197, 31730495). ClinVar contains an entry for this variant (Variation ID: 68346). 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%. This variant disrupts the p.Leu1425 amino acid residue in NF1. Other variant(s) that disrupt this residue have been observed in individuals with NF1-related conditions (PMID: 30530636), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics RCV000059199 SCV001879396 likely pathogenic not provided 2024-07-30 criteria provided, single submitter clinical testing This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with neurofibromatosis type 1 (NF1). Polyphen and MutationTaster predict this amino acid change may be damaging to the protein.
GeneDx RCV000059199 SCV004014216 likely pathogenic not provided 2024-08-25 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies suggest this variant leads to reductions in RAS GAP activity and NF1 expression (Douben H et al. (2023) Hindawi Human Mutation. 2023 (Article ID 9628049):1-14); This variant is associated with the following publications: (PMID: 33794220, 29680440, 10712197, 10220149, 10607834, 31730495, 9668168, 22807134, 25486365, 30530636, 12807981, 18546366, Douben2023[Functional study])
Genetics and Molecular Pathology, SA Pathology RCV001379175 SCV004175361 pathogenic Neurofibromatosis, type 1 2022-04-07 criteria provided, single submitter clinical testing
UniProtKB/Swiss-Prot RCV000059199 SCV000090728 not provided not provided no assertion provided not provided

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