Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000476269 | SCV000541984 | pathogenic | Neurofibromatosis, type 1 | 2022-02-24 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 404431). For these reasons, this variant has been classified as Pathogenic. 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. This missense change has been observed in individuals with neurofibromatosis type 1 (NF1) (PMID: 23656349, 24932921, 29290338; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 845 of the NF1 protein (p.Cys845Arg). |
Center for Human Genetics, |
RCV000476269 | SCV000781953 | pathogenic | Neurofibromatosis, type 1 | 2016-11-01 | criteria provided, single submitter | clinical testing | |
Medical Genomics Laboratory, |
RCV000476269 | SCV000999168 | pathogenic | Neurofibromatosis, type 1 | 2019-06-05 | criteria provided, single submitter | clinical testing | |
Illumina Laboratory Services, |
RCV000476269 | SCV001451561 | pathogenic | Neurofibromatosis, type 1 | 2019-03-26 | criteria provided, single submitter | clinical testing | The NF1 c.2533T>C (p.Cys845Arg) variant is a missense variant that has been reported in at least two studies, in which it is found in a heterozygous state in a total of five individuals with neurofibromatosis type 1 (NF1), including in a mother and daughter pair (Paria et al. 2015; Kockowska et al. 2017). The p.Cys845Arg variant is located in the five-residue cysteine-serine-rich domain in exon 21 of the NF1 gene and is a hotspot for pathogenic missense variants. Additionally, it has been suggested that individuals with pathogenic missense variants in this domain tend to display relatively severe phenotypes and may be at greater risk of known complication of NF1 including symptomatic plexiform, spinal and optic nerve tumors as well as malignancies when compared to affected individuals with pathogenic variants occurring outside of this region (Kockowska et al. 2017). The p.Cys845Arg variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence and application of the ACMG criteria, the p.Cys845Arg variant is classified as pathogenic for neurofibromatosis type 1. |
Genome- |
RCV000476269 | SCV002561781 | pathogenic | Neurofibromatosis, type 1 | 2022-03-15 | criteria provided, single submitter | clinical testing |