Submissions for variant NM_001083116.3(PRF1):c.666C>A (p.His222Gln)

gnomAD frequency: 0.00006  dbSNP: rs751247865

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000349901	SCV000329968	pathogenic	not provided	2016-01-08	criteria provided, single submitter	clinical testing	The H222Q pathogenic variant in the PRF1 gene has been reported previously in individuals with familial hemophagocytic lymphohistiocytosis, in both the homozygous and compound heterozygous states (Molleran et al., 2004; Zur Stadt et al., 2006; Bryceson et al., 2007). Functional studies found that cells expressing the H222Q variant had no detectable cytotoxic activity (Voskoboinik et al., 2005; Chia et al., 2009). The H222Q variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The H222Q variant is a semi-conservative amino acid substitution, which occurs at a position that is conserved across species. We interpret H222Q as a pathogenic variant.
Invitae	RCV000554706	SCV000644890	pathogenic	Familial hemophagocytic lymphohistiocytosis 2	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 222 of the PRF1 protein (p.His222Gln). This variant is present in population databases (rs751247865, gnomAD 0.01%). This missense change has been observed in individuals with hemophagocytic lymphohistiocytosis (PMID: 14757862, 15205266, 16278825, 17525286, 19595804). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 280112). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PRF1 protein function. Experimental studies have shown that this missense change affects PRF1 function (PMID: 15755897, 17525286, 19487666). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844108	SCV002103579	pathogenic	Familial hemophagocytic lymphohistiocytosis	2022-02-15	criteria provided, single submitter	clinical testing	Variant summary: PRF1 c.666C>A (p.His222Gln) 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 3.6e-05 in 249592 control chromosomes (gnomAD). c.666C>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Familial Hemophagocytic Lymphohistiocytosis and the variant segregated with the disease (examples: Karandikar_2007 and Vermeulen_2009, Voskoboinik_2005, Chia_2009). These data indicate that the variant is very likely to be associated with disease. Functional studies showed this variant results in normal expression of perforin but no detectable cytotoxic activity in transfected cells (Voskoboinik_2005, Chia_2009). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002500969	SCV002811733	likely pathogenic	Aplastic anemia; Familial hemophagocytic lymphohistiocytosis 2; Lymphoma, non-Hodgkin, familial	2022-04-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003475886	SCV004204181	pathogenic	Aplastic anemia	2023-10-25	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000349901	SCV001977839	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000349901	SCV001980361	uncertain significance	not provided		no assertion criteria provided	clinical testing