ClinVar Genomic variation as it relates to human health

The PRF1 c.50delT (p.Leu17ArgfsTer34) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Leu17ArgfsTer34 variant has been described in four studies in which it is found in a homozygous state in 36 probands and in a compound heterozygous state in 11 probands (Stepp et al. 1999; Lee et al. 2006; Trizzino et al. 2008; Higa et al. 2013). The p.Leu17ArgfsTer34 variant was reported in seven of 58 control chromosomes and is reported at a reported frequency of 0.003926 in the African population of the Exome Aggregation Consortium. Individuals who were homozygous for the variant were found to have absent NK cytolytic activity, individuals who were compound heterozygotes for the variant were shown to have activity levels of between 1 - 5% of wild type. Perforin expression was severely reduced or undetectable (Stepp et al. 1999; Lee et al. 2006; Trizzino et al. 2008; Higa et al. 2013). Haplotype analysis showed that the p.Leu17ArgfsTer34 variant is inherited as part of a common haplotype, commonly seen in affected individuals of African descent associated with an earlier age of onset compared to other variants in the PRF1 gene (Lee et al. 2006). Based on the potential impact of truncating variants and collective evidence, the p.Leu17ArgfsTer34variant is classified as pathogenic for familial hemophagocytic lymphohistiocytosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Variant summary: PRF1 c.50delT (p.Leu17ArgfsX34) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00024 in 231966 control chromosomes and at a frequency of 0.0032 among individuals of African descent. c.50delT has been reported in the literature in multiple individuals affected with Familial Hemophagocytic Lymphohistiocytosis (example, Stepp_1999, Sanchez_2012, Higa_2013, Zhang_2014, Wojcik_2019). At-least one of these reports suggests a potential digenic mode of inheritance of FHL as a result of a synergistic function effect within genes involved in cytotoxic lymphocyte degranulation (Zhang_2014). It has also been reported as a well recognized cause of Familial Hemophagocytic Lymphohistiocytosis among individuals of African descent (Lee_2006). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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.

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 16860143, 10583959, 29239076, 17873118, 23255033, 22437823, 24916509, 30487145, 31395954, 29625052, 32542393, 34083498, 33570715, 14757862, 31589614)

This frameshifting variant in exon 2 of 3 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Loss-of-function variation in PRF1 is an established mechanism of disease (PMID:17873118). This variant has been previously reported as a homozygous and compound heterozygous change in individuals with familial hemophagocytic lymphohistiocytosis (PMID: 10583959, 22437823, 23255033, 29239076, 34083498). The c.50del (p.Leu17ArgfsTer34) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.03% (87/263362) and thus is presumed to be rare. Based on the available evidence, c.50del (p.Leu17ArgfsTer34) is classified as Pathogenic.

This sequence change creates a premature translational stop signal (p.Leu17Argfs*34) in the PRF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PRF1 are known to be pathogenic (PMID: 1156555, 16860143). This variant is present in population databases (rs147035858, gnomAD 0.3%). This premature translational stop signal has been observed in individual(s) with familial hemophagocytic lymphohistiocytosis (FHL) (PMID: 10583959, 14757862, 16860143, 17873118, 22437823, 23255033). It is commonly reported in individuals of African ancestry (PMID: 10583959, 14757862, 16860143, 17873118, 22437823, 23255033). ClinVar contains an entry for this variant (Variation ID: 468305). For these reasons, this variant has been classified as Pathogenic.

The PRF1 c.50delT variant is predicted to result in a frameshift and premature protein termination (p.Leu17Argfs*34). This variant has been reported to be causative for recessive familial hemophagocytic lymphohistiocytosis (FHL) in several studies (Stepp et al. 1999. PubMed ID: 10583959; Molleran Lee et al. 2004. PubMed ID: 14757862). This variant has been reported to be found at a high frequency among FHL patients of African descent (Lee et al. 2006. PubMed ID: 16860143), and is reported in 0.34% of alleles in individuals of African descent in gnomAD. Frameshift variants in PRF1 are expected to be pathogenic. This variant is interpreted as pathogenic.

High frequency in African American population [Lee et al 2006]