Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001321952 | SCV001512804 | likely pathogenic | Familial hemophagocytic lymphohistiocytosis 2 | 2024-07-22 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 299 of the PRF1 protein (p.Arg299Cys). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with hemophagocytic lymphohistiocytosis (PMID: 14757862, 32542393; Invitae). ClinVar contains an entry for this variant (Variation ID: 1022083). 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 PRF1 protein function. Experimental studies have shown that this missense change affects PRF1 function (PMID: 15755897, 16374518). This variant disrupts the p.Arg299 amino acid residue in PRF1. Other variant(s) that disrupt this residue have been observed in individuals with PRF1-related conditions (PMID: 26450956), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Baylor Genetics | RCV003462895 | SCV004206490 | pathogenic | Aplastic anemia | 2023-03-21 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004699307 | SCV005203428 | pathogenic | Familial hemophagocytic lymphohistiocytosis | 2024-07-18 | criteria provided, single submitter | clinical testing | Variant summary: PRF1 c.895C>T (p.Arg299Cys) results in a non-conservative amino acid change located in the Membrane attack complex component/perforin (MACPF) domain (IPR020864) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251454 control chromosomes. c.895C>T has been reported in the literature in individuals affected with Familial Hemophagocytic Lymphohistiocytosis (examples:Gadoury-Levesque_2020,Voskoboinik_2005). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Voskoboinik_2005). The following publications have been ascertained in the context of this evaluation (PMID: 32542393, 15755897). ClinVar contains an entry for this variant (Variation ID: 1022083). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Fulgent Genetics, |
RCV005050331 | SCV005674846 | likely pathogenic | Aplastic anemia; Familial hemophagocytic lymphohistiocytosis 2; Lymphoma, non-Hodgkin, familial | 2024-05-13 | criteria provided, single submitter | clinical testing |