Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000685816 | SCV000813314 | uncertain significance | Familial hemophagocytic lymphohistiocytosis 2 | 2024-10-07 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 250 of the PRF1 protein (p.Thr250Met). This variant is present in population databases (rs775966864, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PRF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 566088). 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 PRF1 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. |
| Genomic Medicine Center of Excellence, |
RCV000685816 | SCV005374505 | uncertain significance | Familial hemophagocytic lymphohistiocytosis 2 | 2024-09-22 | criteria provided, single submitter | clinical testing | |
| Department of Pathology and Laboratory Medicine, |
RCV001355294 | SCV001550137 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The PRF1 p.Thr250Met variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs775966864), Cosmic and ClinVar (classified as a VUS by Invitae for Hemophagocytic lymphohistiocytosis, familial, 2). The variant was also identified in control databases in 12 of 282802 chromosomes at a frequency of 0.000042 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 4 of 24972 chromosomes (freq: 0.00016), South Asian in 3 of 30616 chromosomes (freq: 0.000098), East Asian in 1 of 19954 chromosomes (freq: 0.00005) and European (non-Finnish) in 4 of 129114 chromosomes (freq: 0.000031), but was not observed in the Latino, Ashkenazi Jewish, European (Finnish) or Other populations. The p.Thr250 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |