ClinVar

Description

Variant summary: PRF1 c.797T>C (p.Ile266Thr) 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 251436 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.797T>C has been reported in the literature as a compound heterozygous genotype with c.272C>T (p.Ala91Val) in at-least one individual affected with Familial Hemophagocytic Lymphohistiocytosis (example, Tesi_2015). However, the same genotype was also detected in the unaffected elder sister of this individual. This variant has been subsequently cited by others as being associated with a late onset presentation of Familial Hemophagocytic Lymphohistiocytosis (Benezech_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hemophagocytic Lymphohistiocytosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.