ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.4262C>T (p.Pro1421Leu)

gnomAD frequency: 0.00002  dbSNP: rs753997885
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000472778 SCV000541992 uncertain significance Neurofibromatosis, type 1 2023-09-27 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1400 of the NF1 protein (p.Pro1400Leu). This variant is present in population databases (rs753997885, gnomAD 0.009%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 24448499). ClinVar contains an entry for this variant (Variation ID: 404437). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV002318499 SCV000670481 uncertain significance Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2021-11-16 criteria provided, single submitter clinical testing The p.P1400L variant (also known as c.4199C>T), located in coding exon 31 of the NF1 gene, results from a C to T substitution at nucleotide position 4199. The proline at codon 1400 is replaced by leucine, an amino acid with similar properties. This alteration was observed with an allele frequency of 0.0000 in 53 unselected male breast cancer patients and was observed with an allele frequency of 0.0001 in 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Mendelics RCV000472778 SCV000839147 uncertain significance Neurofibromatosis, type 1 2018-07-02 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000572685 SCV002527563 uncertain significance Hereditary cancer-predisposing syndrome 2022-01-22 criteria provided, single submitter curation
Genome-Nilou Lab RCV000472778 SCV002560401 uncertain significance Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing

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