ClinVar

Description

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.