ClinVar Miner

Submissions for variant NM_001083116.3(PRF1):c.886T>C (p.Tyr296His)

gnomAD frequency: 0.00002  dbSNP: rs148237800
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001040065 SCV001203620 uncertain significance Familial hemophagocytic lymphohistiocytosis 2 2021-08-28 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 296 of the PRF1 protein (p.Tyr296His). The tyrosine residue is moderately conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs148237800, ExAC 0.003%). This missense change has been observed in individual(s) with familial hemophagocytic lymphohistiocytosis (PMID: 26450956). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001797814 SCV002041615 uncertain significance not specified 2021-11-03 criteria provided, single submitter clinical testing Variant summary: PRF1 c.886T>C (p.Tyr296His) results in a conservative amino acid change located in the Membrane attack complex component/perforin (MACPF) domain (IPR020864) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251456 control chromosomes. c.886T>C has been reported in the literature as a compound heterozygous genotype in at-least three individuals affected with Familial hemophagocytic lymphohistiocytosis (example, Abdalgani_2015, Gadoury-Levesque_2020) and as a non-informative genotype in at-least one individual with systemic Juvenile Idiopathic Arthritis (SJIA) who underwent whole exome sequencing analysis (Kaufman_2014). The clinical presentation corroborated with the analysis of perforin mean channel fluorescence measurements in peripheral blood natural killer (NK) cells by flow cytometry in at-least two of the affected biallelic individuals reported in the literature (example, Abdalgani_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV002261256 SCV002542804 uncertain significance Autoinflammatory syndrome 2018-04-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV003473620 SCV004204183 likely pathogenic Aplastic anemia 2023-10-22 criteria provided, single submitter clinical testing

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