ClinVar

Description

Variant summary: PRF1 c.853_855delAAG (p.Lys285del) results in an in-frame deletion that is predicted to remove one amino acid from the Membrane attack complex component/perforin (MACPF) domain (IPR020864) of the encoded protein. The variant allele was found at a frequency of 3.2e-05 in 251356 control chromosomes. c.853_855delAAG has been reported in the literature as biallelic homozygous or compound heterozygous genotype in multiple individuals affected with Familial Hemophagocytic Lymphohistiocytosis (example, PMID: 22186995, 34992599, 26184781, 31388699). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, PMID: 22186995). The most pronounced variant effect results in complete abolishment of perforin cytotoxicity as well as low or absent NK cell activity in homozygous genotype (example, PMID: 26184781). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.