Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000806033 | SCV000946013 | uncertain significance | Neurofibromatosis, type 1 | 2024-07-24 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2612 of the NF1 protein (p.Glu2612Lys). 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: 650807). 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. |
| St. |
RCV000806033 | SCV002584634 | uncertain significance | Neurofibromatosis, type 1 | 2022-09-09 | criteria provided, single submitter | clinical testing | The NF1 c.7834G>A (p.Glu2612Lys) missense change has a maximum subpopulation frequency of 0.0080% 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. |
| Ambry Genetics | RCV002406797 | SCV002670840 | uncertain significance | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2023-09-11 | criteria provided, single submitter | clinical testing | The p.E2612K variant (also known as c.7834G>A), located in coding exon 53 of the NF1 gene, results from a G to A substitution at nucleotide position 7834. The glutamic acid at codon 2612 is replaced by lysine, an amino acid with similar properties. This amino acid position is well 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 this alteration remains unclear. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV005240594 | SCV005884511 | uncertain significance | not specified | 2024-12-24 | criteria provided, single submitter | clinical testing | Variant summary: NF1 c.7834G>A (p.Glu2612Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251306 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7834G>A in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27069254, 10678181, 23460398, 29872168, NCCN_MDS). ClinVar contains an entry for this variant (Variation ID: 650807). Based on the evidence outlined above, the variant was classified as uncertain significance. |