ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.269T>C (p.Leu90Pro)

dbSNP: rs1555605393
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001062713 SCV001227529 pathogenic Neurofibromatosis, type 1 2021-10-16 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 90 of the NF1 protein (p.Leu90Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with clinical features of neurofibromatosis type I (PMID: 17426081, 30046999; Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency).
Ambry Genetics RCV002429699 SCV002742729 likely pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2023-01-27 criteria provided, single submitter clinical testing The p.L90P variant (also known as c.269T>C), located in coding exon 3 of the NF1 gene, results from a T to C substitution at nucleotide position 269. The leucine at codon 90 is replaced by proline, an amino acid with similar properties. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been identified in multiple individuals meeting clinical diagnostic criteria for neurofibromatosis type 1 (NF1) (Bausch B et al. J Clin Endocrinol Metab, 2007 Jul;92:2784-92; Xiao H et al. J Mol Neurosci, 2018 Aug;65:557-563). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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