ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.3757C>T (p.Leu1253Phe)

dbSNP: rs2067186931
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001299802 SCV001488914 uncertain significance Neurofibromatosis, type 1 2024-03-20 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1253 of the NF1 protein (p.Leu1253Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1003270). 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%. 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 RCV004557516 SCV005047770 uncertain significance Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2023-09-05 criteria provided, single submitter clinical testing The p.L1253F variant (also known as c.3757C>T), located in coding exon 28 of the NF1 gene, results from a C to T substitution at nucleotide position 3757. The leucine at codon 1253 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration was detected in 1/1054 Hispanic BRCA1/2-negative probands with hereditary breast cancer and 0/1189 controls (Weitzel JN et al. Cancer, 2019 Aug;125:2829-2836). 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.

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