ClinVar Miner

Submissions for variant NM_001083116.3(PRF1):c.659G>A (p.Gly220Asp)

gnomAD frequency: 0.00001  dbSNP: rs202217604
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV000988374 SCV001138064 likely pathogenic Familial hemophagocytic lymphohistiocytosis 2 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001797807 SCV002041614 uncertain significance not specified 2021-11-16 criteria provided, single submitter clinical testing Variant summary: PRF1 c.659G>A (p.Gly220Asp) 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 8e-06 in 249148 control chromosomes. c.659G>A has been reported in the literature as a homozygous genotype in at-least one comprehensively genotyped individual affected with Familial Hemophagocytic Lymphohistiocytosis and has been subsequently cited by others (example, Tesi_2015, Gadoury-Levesque_2020). 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 likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000988374 SCV003441620 pathogenic Familial hemophagocytic lymphohistiocytosis 2 2024-12-24 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 220 of the PRF1 protein (p.Gly220Asp). This variant is present in population databases (rs202217604, gnomAD 0.006%). This missense change has been observed in individuals with PRF1-related conditions (PMID: 26684649, 32542393). ClinVar contains an entry for this variant (Variation ID: 802582). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PRF1 protein function with a positive predictive value of 95%. This variant disrupts the p.Gly220 amino acid residue in PRF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17873118, 21931115; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV003473535 SCV004204204 likely pathogenic Aplastic anemia 2023-08-10 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005047163 SCV005674928 likely pathogenic Aplastic anemia; Familial hemophagocytic lymphohistiocytosis 2; Lymphoma, non-Hodgkin, familial 2024-02-05 criteria provided, single submitter clinical testing

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