Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV003338693 | SCV000743030 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-07-13 | criteria provided, single submitter | clinical testing | The c.5549T>C (p.V1850A) alteration is located in coding exon 38 of the NF1 gene. This alteration results from a T to C substitution at nucleotide position 5549, causing the valine (V) at amino acid position 1850 to be replaced by an alanine (A). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). The p.V1850 amino acid is located within the leucine-rich repeat domain (LRD) of NF1, which is involved in neuronal differentiation via interactions with the VCP protein (Wang, 2011). This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV005091818 | SCV005821109 | uncertain significance | Neurofibromatosis, type 1 | 2024-09-12 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1829 of the NF1 protein (p.Val1829Ala). 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: 522137). 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 expected to disrupt NF1 protein function with a positive 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. |