ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.2576G>C (p.Gly859Ala)

gnomAD frequency: 0.00001  dbSNP: rs876659829
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213294 SCV000276701 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-17 criteria provided, single submitter clinical testing The p.G859A variant (also known as c.2576G>C), located in coding exon 21 of the NF1 gene, results from a G to C substitution at nucleotide position 2576. The glycine at codon 859 is replaced by alanine, an amino acid with 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 6501 samples (13002 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 55000alleles tested) in our clinical cohort.This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis.Since supporting evidence is limited at this time, the clinical significance of p.G859Aremains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000689148 SCV000816788 uncertain significance Neurofibromatosis, type 1 2024-06-04 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 859 of the NF1 protein (p.Gly859Ala). 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: 232542). 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 not expected to disrupt NF1 protein function with a negative 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.
GeneDx RCV001753670 SCV002005378 uncertain significance not provided 2019-05-03 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab RCV000689148 SCV002562060 uncertain significance Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing

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