Submissions for variant NM_001083116.3(PRF1):c.272C>T (p.Ala91Val)

gnomAD frequency: 0.02791  dbSNP: rs35947132

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224458	SCV000280651	pathogenic	not provided	2014-08-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000547554	SCV000363438	benign	Familial hemophagocytic lymphohistiocytosis 2	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000456018	SCV000540113	benign	not specified	2016-03-29	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency
GeneDx	RCV000224458	SCV000617803	risk factor	not provided	2021-03-18	criteria provided, single submitter	clinical testing	Identified in individuals with familial hemophagocytic lymphohistiocytosis and acute lymophoblastic leukemia; however, the A91V variant has also been identified in both unaffected relatives and unaffected controls (Zur Stadt et al., 2004; Santoro et al., 2005; An et al., 2013); Functional studies suggest that the A91V variant results in decreased levels of perforin expression, with partial loss of protein function and stability (Voskoboinik et al., 2005; House et al., 2015); This variant is associated with the following publications: (PMID: 33256384, 32150605, 32198610, 32342501, 32542393, 32300447, 31932842, 30957677, 29263817, 30343897, 30287596, 14757862, 24916509, 27622035, 28863861, 27153395, 27872624, 15342365, 23592409, 26597256, 24632576, 22970278, 25937001, 25121636, 24309606, 22437823, 16611257, 25776844, 23073290, 25354579, 18496551, 17311987, 17475905, 15741215, 12229880, 21881043, 15755897, 15921391)
Invitae	RCV000547554	SCV000644881	likely benign	Familial hemophagocytic lymphohistiocytosis 2	2024-02-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000547554	SCV001138067	likely benign	Familial hemophagocytic lymphohistiocytosis 2	2019-05-28	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002260967	SCV002542775	benign	Autoinflammatory syndrome	2022-01-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000456018	SCV002570677	likely benign	not specified	2022-07-13	criteria provided, single submitter	clinical testing	Variant summary: PRF1 c.272C>T (p.Ala91Val) 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 0.029 in 280896 control chromosomes (gnomAD), predominantly at a frequency of 0.046 within the Non-Finnish European subpopulation in the gnomAD database, including 129 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 17 fold of the estimated maximal expected allele frequency for a pathogenic variant in PRF1 causing Familial Hemophagocytic Lymphohistiocytosis phenotype (0.0027), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Experimental evidence using transiently transfected RBL-2H4 cells showed that the variant had approximately half the lytic activity as cells transfected with wild-type, which was further reduced to less than 10-fold activity when using purified A91V protein (Voskoboinik_2007). Primary natural killer cells from otherwise healthy heterozygous volunteers showed that natural killer cells from A91V/WT individuals had >35% reduction in cell killing efficiency compared with WT/WT individuals (House_2015). Six ClinVar submitters have assessed the variant since 2014: one classified the variant as pathogenic, two as likey benign, two as benign, and one as a risk factor. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003398509	SCV004120359	uncertain significance	PRF1-related condition	2024-01-30	criteria provided, single submitter	clinical testing	The PRF1 c.272C>T variant is predicted to result in the amino acid substitution p.Ala91Val. This variant has been studied extensively, but its clinical significance remains unclear. The PRF1 gene variant c.272C>T is found at a high frequency among several control populations (up to 4.6% and in many homozygous individuals; and has been classified as a “neutral polymorphism” (Molleran Lee et al. 2004. PubMed ID: 14757862; Zur Stadt et al. 2004. PubMed ID: 15342365). However, considerable clinical and experimental data support a functional role of the p.Ala91Val variant resulting in reduced cytotoxic activity that may be significant for the pathogenesis of hemophagocytic lymphohistiocytosis and other disorders, including NK/T-Cell lymphomas, in both heterozygous and homozygous carriers of the p.Ala91Val substitution (Voskoboinik et al. 2005. PubMed ID: 15755897; Voskoboinik et al. 2007. PubMed ID: 17475905; Martínez-Pomar et al. 2013. PubMed ID: 23073290; Trambas et al. 2005. PubMed ID: 15741215; Clementi et al. 2002. PubMed ID: 12229880; Santoro et al. 2005. PubMed ID: 15921391; Zhang et al. 2011. PubMed ID: 21881043; Mancebo et al. 2006. PubMed ID: 16956828; House et al. 2015. PubMed ID: 25776844; Manso et al. 2014. PubMed ID: 24632576; Willig et al. 2015. PubMed ID: 25937001, Palterer et al. 2017. PubMed ID: 28863861). Consequently, this allele has also been categorized as either a functional polymorphism or as a risk allele. Due to conflicting reports, the significance of this variant remains uncertain.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000547554	SCV004805429	uncertain significance	Familial hemophagocytic lymphohistiocytosis 2	2024-03-25	criteria provided, single submitter	research
OMIM	RCV000014719	SCV000034974	uncertain significance	Hemophagocytic lymphohistiocytosis, familial, 2, susceptibility to	2007-08-15	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000224458	SCV001550951	likely benign	not provided		no assertion criteria provided	clinical testing	The PRF1 p.Ala91Val variant was identified in the literature, however the role of its pathogenicity has been debated. The variant was identified in 15 of 320 proband chromosomes (frequency: 0.053) from individuals or families with haemophagocytic lymphohistiocytosis (HLH), acquired aplastic anemia, and Dianzani Autoimmune Lymphoproliferative Disease (Molleran_2004_PMID: 14757862, Solomou_2007_PMID: 17311987 & Clementi_2006_PMID: 16720836). The variant has also been reported in control population in multiple studies at frequencies of 0.046, 0.010, 0.0174 and 0.087 (Lek_2016_PMID: 27535533, Zur Stadt_2004_PMID: 15342365; Solomou_2007_PMID: 17311987 & Clementi_2006_PMID: 16720836). The variant was identified in dbSNP (ID: rs35947132) as “With Pathogenic allele”. In ClinVar, there are conflicting interpretations of pathogenicity from six submitters: 1x pathogenic (Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics), 2x likely benign (Illumina Clinical Services Laboratory and Invitae), 1x benign (Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine), and 2x uncertain significance (GeneDx and OMIM). The associated conditions are Hemophagocytic lymphohistiocytosis, familial, 2 and Familial hemophagocytic lymphohistiocytosis. The variant was also identified in LOVD 3.0 but was not found in Cosmic. The variant was identified in control databases in 8191 of 280896 chromosomes (171 homozygous) at a frequency of 0.02916 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 5912 of 128018 chromosomes (freq: 0.04618), Other in 252 of 7176 chromosomes (freq: 0.03512), Ashkenazi Jewish in 273 of 10298 chromosomes (freq: 0.02651), European (Finnish) in 655 of 24848 chromosomes (freq: 0.02636), Latino in 811 of 35320 chromosomes (freq: 0.02296), African in 153 of 24738 chromosomes (freq: 0.006185), South Asian in 132 of 30580 chromosomes (freq: 0.004317), and East Asian in 3 of 19918 chromosomes (freq: 0.000151). Perforin plays a key role in the cytotoxicity of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). A functional study of the p.A91V variant showed that the variant resulted in impaired cleavage of perforin to its active form, resulting in loss of CTL and NK-cell cytotoxicity against targets (Trambas_2005_PMID: 15741215). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. The p.Ala91 residue is not highly conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this varaint. This variant is classified as a variant of likely benign.
GeneReviews	RCV000547554	SCV001976569	not provided	Familial hemophagocytic lymphohistiocytosis 2		no assertion provided	literature only	Variant assoc w/late-onset (adult) fHLH [Carvelli et al 2020, Miller et al 2020]. Common variant in population studies of healthy persons; functional effects were studied [Chia et al 2009].
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000456018	SCV002033872	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000456018	SCV002036159	benign	not specified		no assertion criteria provided	clinical testing