Submissions for variant NM_001083116.3(PRF1):c.1310C>T (p.Ala437Val)

gnomAD frequency: 0.00073  dbSNP: rs138126912

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000701304	SCV000363425	likely pathogenic	Familial hemophagocytic lymphohistiocytosis 2	2017-08-21	criteria provided, single submitter	clinical testing	The PRF1 c.1310C>T (p.Ala437Val) missense variant has been reported in five studies in which it was found in a total of six individuals with familial hemophagocytic lymphohistocytosis including in a compound heterozygous state with another missense variant in two individuals and in a heterozygous state where a second variant was not detected in four individuals including one sib-pair. The variant was also found in a heterozygous state in the unaffected father of the sib-pair (Zhang et al. 2011; Zhang et al. 2014; Willig et al. 2015; Džoljić et al. 2015). Control data are unavailable for this variant which is reported at a frequency of 0.00121 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies showed that the p.Ala437Val variant results in absent NK-cell function and 61% of normal perforin levels (Zhang et al. 2011). Based on the evidence, the p.Ala437Val variant is classified as likely pathogenic for familial hemophagocytic lymphohistocytosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000701304	SCV000830098	uncertain significance	Familial hemophagocytic lymphohistiocytosis 2	2022-10-21	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 437 of the PRF1 protein (p.Ala437Val). This variant is present in population databases (rs138126912, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with suspected familial hemophagocytic lymphohistiocytosis (HLH), atypical HLH, and/or lymphoma of the brain (PMID: 21881043, 25845254, 25937001, 29263817). ClinVar contains an entry for this variant (Variation ID: 300327). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001529197	SCV002009738	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002261036	SCV002542766	uncertain significance	Autoinflammatory syndrome	2018-10-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282115	SCV002572328	uncertain significance	not specified	2022-08-25	criteria provided, single submitter	clinical testing	Variant summary: PRF1 c.1310C>T (p.Ala437Val) results in a non-conservative amino acid change located in the C2 domain (IPR000008) 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 0.00073 in 250636 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PRF1 causing Familial Hemophagocytic Lymphohistiocytosis (0.00073 vs 0.0027), allowing no conclusion about variant significance. c.1310C>T has been reported in the literature as a non-informative genotype (second allele not specified) or in a proposed model of synergistic heterozygosity with a heterozygous variant in a different gene in individuals affected with features of Familial Hemophagocytic Lymphohistiocytosis (FHL)/Primary Lymphoma with a family history of FHL/Omphalocele and Liver failure (example, Zhang_2011, Dolji_2015, Noll_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hemophagocytic Lymphohistiocytosis. 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 (VUS, n=3; Likely pathogenic, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002520610	SCV003583443	uncertain significance	Inborn genetic diseases	2022-09-28	criteria provided, single submitter	clinical testing	The c.1310C>T (p.A437V) alteration is located in exon 3 (coding exon 2) of the PRF1 gene. This alteration results from a C to T substitution at nucleotide position 1310, causing the alanine (A) at amino acid position 437 to be replaced by a valine (V). The p.A437V alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529197	SCV001742260	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001529197	SCV001967735	uncertain significance	not provided		no assertion criteria provided	clinical testing