ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.7487C>G (p.Ser2496Cys)

gnomAD frequency: 0.00001  dbSNP: rs371773406
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166659 SCV000217464 uncertain significance Hereditary cancer-predisposing syndrome 2015-08-11 criteria provided, single submitter clinical testing The p.S2496C variant (also known as c.7487C>G), located in coding exon 51 of the NF1 gene, results from a C to G substitution at nucleotide position 7487. The serine at codon 2496 is replaced by cysteine, an amino acid with dissimilar properties. This variant was previously reported in the SNPDatabase as rs371773406. Based on data from the NHLBI Exome Sequencing Project (ESP), the G allele has an overall frequency of approximately 0.01% (1/13006) total alleles studied, having been observed in 0.02% (1/4406) African American alleles. To date, this alteration has been detected with an allele frequency of approximately 0.004% (greater than 55000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.S2496C remains unclear.
Invitae RCV000198334 SCV000254513 uncertain significance Neurofibromatosis, type 1 2024-01-26 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2475 of the NF1 protein (p.Ser2475Cys). This variant is present in population databases (rs371773406, gnomAD 0.007%). 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: 186986). 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 80%. 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.
Genome-Nilou Lab RCV000198334 SCV002561089 uncertain significance Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing
GeneDx RCV002460944 SCV002756760 uncertain significance not provided 2022-11-21 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter 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)
Fulgent Genetics, Fulgent Genetics RCV002492671 SCV002785411 uncertain significance Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis 2022-01-25 criteria provided, single submitter clinical testing

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