ClinVar Genomic variation as it relates to human health

Viafet Genomics Laboratory has identified this variant in a homozygous state in a child presenting with sepsis-like syndrome, hepatosplenomegaly, hypofibrinogenemia, hypoalbuminemia, hypertriglyceridemia, pancytopenia, a very high ferritin level and high direct bilirubin level. In addition, this variant has been identified in a homozygous state in patients affected with familial hemophagocytic lymphohistiocytosis (PMIDs: 10583959 and 20197201). This variant is present in exon 2/2 in a position that is conserved across both transcripts of this gene (2/2). Several loss-of-function variants are reported as disease-causing in HGMD and/or ClinVar after this position.

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 182 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 12229880, 12764739, 23274377, 20197201, 10583959, 15728124, 31514334, 34083498, 34426522, 31589614, 33746956, 35023663, 16278825)

This nonsense variant is found in the last exon of PRF1 and is therefore predicted to escape nonsense-mediated mRNA decay (NMD). However, nonsense variants located downstream of this variant have been reported as disease-causing variants in the literature (PMID: 17873118). This is a known Pathogenic variant that has been previously reported as a homozygous change in patients with familial hemophagocytic lymphohistiocytosis (PMID: 10583959, 20197201, 33746956). Loss-of-function variation in PRF1 is an established mechanism of disease (PMID: 17873118). The c.1122G>A (p.Trp374Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (4/245272) and thus is presumed to be rare. Based on the available evidence, the c.1122G>A (p.Trp374Ter) variant is classified as Pathogenic.

The c.1122G>A (p.W374*) alteration, located in exon 3 (coding exon 2) of the PRF1 gene, consists of a G to A substitution at nucleotide position 1122. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 374. This alteration occurs at the 3' terminus of the PRF1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 33% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). Based on data from the Genome Aggregation Database (gnomAD) database, the PRF1 c.1122G>A alteration was observed in 0.0016% (4/245272) of total alleles studied, with a frequency of 0.0036% (4/110234) in the European (non-Finnish) subpopulation. This alteration has been reported in the homozygous state in several patients with familial hemophagocytic lymphohistiocytosis and is seen more frequently in the Turkish population (Stepp, 1999; Zur Stadt, 2006; Balta, 2010). Cells from an affected patient showed greatly reduced cytolytic activity and complete absence of perforin protein (Stepp, 1999). This alteration has also been reported in the compound heterozygous state in an Omani patient with familial hemophagocytic lymphohistiocytosis (Muralitharan, 2007). Based on the available evidence, this alteration is classified as pathogenic.

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000013709 / PMID: 10583959). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

This sequence change creates a premature translational stop signal (p.Trp374*) in the PRF1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 182 amino acid(s) of the PRF1 protein. This variant is present in population databases (rs104894176, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with hemophagocytic lymphohistiocytosis (PMID: 10583959, 11565555, 16278825, 20197201). ClinVar contains an entry for this variant (Variation ID: 13709). This variant disrupts a region of the PRF1 protein in which other variant(s) (p.Cys497*) have been determined to be pathogenic (PMID: 11841437). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

High prevalence in Turkish persons [Zur Stadt et al 2006]