Submissions for variant NM_001083116.3(PRF1):c.368G>A (p.Arg123His)

gnomAD frequency: 0.00044  dbSNP: rs139336186

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000972179	SCV001119874	likely benign	Familial hemophagocytic lymphohistiocytosis 2	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000972179	SCV001259244	uncertain significance	Familial hemophagocytic lymphohistiocytosis 2	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genetic Services Laboratory, University of Chicago	RCV001819121	SCV002070208	uncertain significance	not specified	2021-11-29	criteria provided, single submitter	clinical testing	DNA sequence analysis of the PRF1 gene demonstrated a sequence change, c.368G>A, in exon 2 that results in an amino acid change, p.Arg123His. This sequence change does not appear to have been previously described in individual(s) with anaplastic large cell lymphoma (PMIDs: 17477373 and 24309606). This sequence change has been described in the gnomAD database with a frequency of 0.51% in the Ashkenazi Jewish subpopulation (dbSNP rs139336186). The p.Arg123His change affects a poorly conserved amino acid residue located in a domain of the PRF1 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg123His substitution. Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Arg123His change remains unknown at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001819121	SCV002103580	uncertain significance	not specified	2022-02-25	criteria provided, single submitter	clinical testing	Variant summary: PRF1 c.368G>A (p.Arg123His) results in a non-conservative amino acid change located in the Membrane attack complex component/perforin (MACPF) domain (IPR020864) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00052 in 248100 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PRF1 causing Familial Hemophagocytic Lymphohistiocytosis (0.00052 vs 0.0027), allowing no conclusion about variant significance. Although reported in the literature in association with Anaplastic large cell lymphoma (HGMD database), to our knowledge, no occurrence of c.368G>A in individuals affected with Familial Hemophagocytic Lymphohistiocytosis and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=1, VUS, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002261244	SCV002542777	uncertain significance	Autoinflammatory syndrome	2018-10-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003413765	SCV004113753	uncertain significance	PRF1-related condition	2023-04-25	criteria provided, single submitter	clinical testing	The PRF1 c.368G>A variant is predicted to result in the amino acid substitution p.Arg123His. The variant has been reported in individuals with anaplastic large cell lymphoma, although no further evidence was provided to determine its pathogenicity (Cannella et al. 2007. PubMed ID: 17477373; Ciambotti et al. 2014. PubMed ID: 24309606). The variant has also been reported as a "polymorphism" in one study of individuals with familial hemophagocytic lymphohistiocytosis (Molleran et al. 2004. PubMed ID: 14757862). This variant is reported in 0.51% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-72360291-C-T). In ClinVar, this variant has conflicting interpretations of likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/789535/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001729772	SCV001977823	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001729772	SCV001980319	uncertain significance	not provided		no assertion criteria provided	clinical testing