Submissions for variant NM_001042492.3(NF1):c.7700C>T (p.Pro2567Leu)

gnomAD frequency: 0.00001  dbSNP: rs754511534

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217495	SCV000278760	uncertain significance	Hereditary cancer-predisposing syndrome	2015-10-06	criteria provided, single submitter	clinical testing	The p.P2567L variant (also known as c.7700C>T), located in coding exon 52 of the NF1 gene, results from a C to T substitution at nucleotide position 7700. The proline at codon 2567 is replaced by leucine, an amino acid with somewhat similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately X.002% (greater than 55000alleles tested) in our clinical cohort.This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and yet tolerated by PolyPhen and SIFT in silico analyses, respectively.Since supporting evidence is limited at this time, the clinical significance of pP2567Lremains unclear.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000660118	SCV000782108	likely pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Invitae	RCV000660118	SCV000836245	uncertain significance	Neurofibromatosis, type 1	2023-02-09	criteria provided, single submitter	clinical testing	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. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2546 of the NF1 protein (p.Pro2546Leu). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 234225). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NF1 protein function.
GeneDx	RCV002509324	SCV002818946	uncertain significance	not provided	2022-07-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25486365)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000660118	SCV004031120	uncertain significance	Neurofibromatosis, type 1	2023-08-16	criteria provided, single submitter	clinical testing	The NF1 c.7637C>T (p.Pro2546Leu) missense change has a maximum subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Neurofibromatosis type 1. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.