Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000216796 | SCV000274340 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-03-09 | criteria provided, single submitter | clinical testing | Thep.E1121Gvariant (also known as c.3362A>G), located in coding exon 26 of theNF1gene, results from an A to G substitution at nucleotide position 3362. The glutamic acid at codon 1121 is replaced by glycine, an amino acid with similar properties. This alteration was reported in a father/son pair. Both of these individuals were described as having multiple café-au-lait spots, however, no other NF1-related clinical features were noted. The authors state that this exonic alteration produced mosaicism of E1121G and exon 20 (coding exon 26) skipping at the mRNA level due to a decreased ratio of ESE/ESSs. The mosaicism of the post-transcriptional profile was further examined using real-time PCR with cDNA obtained from this family; this assay demonstrated the skipping rate of the mutant exon in both individuals. The authors conclude that this is a disease causing mutation (Xu W,Int. J. Mol. Med.2014 Jul; 34(1):53-60.).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 0.003% (greater than 30000 alleles tested) in our clinical cohort. Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of p.E1121G remains unclear. |
| Labcorp Genetics |
RCV000470964 | SCV000542052 | uncertain significance | Neurofibromatosis, type 1 | 2023-12-05 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1121 of the NF1 protein (p.Glu1121Gly). This variant is present in population databases (rs757222815, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of NF1-related conditions (PMID: 24789688). ClinVar contains an entry for this variant (Variation ID: 230699). 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. 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- |
RCV000470964 | SCV002560287 | uncertain significance | Neurofibromatosis, type 1 | 2022-03-15 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV003165559 | SCV003897059 | benign | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2022-12-02 | criteria provided, single submitter | clinical testing | This alteration is classified as 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. |