Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000312372 | SCV000363432 | uncertain significance | Familial hemophagocytic lymphohistiocytosis 2 | 2017-04-27 | criteria provided, single submitter | clinical testing | The PRF1 c.695G>A (p.Arg232His) missense variant has been described in six studies in individuals with familial hemophagocytic lymphohistiocytosis (FHL) (Feldman et al. 2002; Zur Stadt et al. 2006; Busiello et al. 2007; Cannella et al. 2007; Zhang et al. 2011; Sieni et al. 2012). The p.Arg232His variant was detected in a compound heterozygous state with a missense variant in two individuals and in a compound heterozygous state as part of a complex allele involving a p.Ala91Val variant in an additional five individuals. One unaffected individual was also found to be compound heterozygous for the p.Arg232His and p.Ala91Val variants, though not as part of a complex allele. The p.Arg232His variant was further detected in a heterozygous state in two affected individuals. The p.Arg232His variant was absent from 50 controls but is reported at a frequency of 0.00042 in the South Asian population of the Exome Aggregation Consortium. Functional studies demonstrated that the p.Arg232His variant resulted in reduced or no detectable perforin expression, only partial processing to the mature form of the protein, and only 27 – 30% of wild type cytotoxic activity (Feldman et al. 2002; Voskoboinik et al. 2005; Risma et al. 2006; Zhang et al. 2011; Sieni E et al. 2012). The complex allele was shown to be completely inactive (Voskoboinik et al. 2005). The evidence for this variant in isolation is limited. The p.Arg232His variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for familial hemophagocytic lymphohistiocytosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Invitae | RCV000312372 | SCV001398068 | pathogenic | Familial hemophagocytic lymphohistiocytosis 2 | 2024-01-02 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 232 of the PRF1 protein (p.Arg232His). This variant is present in population databases (rs747380397, gnomAD 0.03%). This missense change has been observed in individual(s) with anaplastic large cell lymphoma and hemophagocytic lymphohistiocytosis and/or hemophagocytic lymphohistiocytosis (PMID: 12060139, 14739222, 16278825, 21881043, 22970278, 24309606, 26342526; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 300331). 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, 19487666). This variant disrupts the p.Arg232 amino acid residue in PRF1. Other variant(s) that disrupt this residue have been observed in individuals with PRF1-related conditions (PMID: 33225392, 33746956), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| Genome Diagnostics Laboratory, |
RCV002261037 | SCV002542793 | uncertain significance | Autoinflammatory syndrome | 2018-07-01 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV003475926 | SCV004204193 | pathogenic | Aplastic anemia | 2023-09-30 | criteria provided, single submitter | clinical testing |