Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000219219 | SCV000273399 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-11-10 | criteria provided, single submitter | clinical testing | The p.N730H variant (also known as c.2188A>C), located in coding exon 18 of the NF1 gene, results from an A to C substitution at nucleotide position 2188. The asparagine at codon 730 is replaced by histidine, 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 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 110000alleles tested) in our clinical cohort.This amino acid position is not 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.N730Hremains unclear. |
| Labcorp Genetics |
RCV000469957 | SCV000542132 | uncertain significance | Neurofibromatosis, type 1 | 2024-11-19 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 730 of the NF1 protein (p.Asn730His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 229999). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. |
| Genome- |
RCV000469957 | SCV002562007 | uncertain significance | Neurofibromatosis, type 1 | 2022-03-15 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV003462419 | SCV004198301 | uncertain significance | Juvenile myelomonocytic leukemia | 2023-09-20 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV004558476 | SCV005047529 | likely benign | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2023-12-04 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |