ClinVar Miner

Submissions for variant NM_001083116.3(PRF1):c.1262T>G (p.Phe421Cys)

gnomAD frequency: 0.00014  dbSNP: rs200534908
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000792321 SCV000931608 likely benign Familial hemophagocytic lymphohistiocytosis 2 2024-12-24 criteria provided, single submitter clinical testing
Mendelics RCV000792321 SCV001138062 uncertain significance Familial hemophagocytic lymphohistiocytosis 2 2019-05-28 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002487642 SCV002784801 uncertain significance Aplastic anemia; Familial hemophagocytic lymphohistiocytosis 2; Lymphoma, non-Hodgkin, familial 2022-03-25 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV003130039 SCV003809854 uncertain significance not provided 2020-03-12 criteria provided, single submitter clinical testing
GeneDx RCV003130039 SCV004168897 uncertain significance not provided 2023-10-31 criteria provided, single submitter clinical testing See Variant Classification Assertion Criteria.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004782551 SCV005395082 uncertain significance not specified 2024-09-10 criteria provided, single submitter clinical testing Variant summary: PRF1 c.1262T>G (p.Phe421Cys) 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 0.00031 in 249688 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PRF1 causing Familial Hemophagocytic Lymphohistiocytosis (0.00031 vs 0.0027), allowing no conclusion about variant significance. c.1262T>G has been reported in the literature in individuals affected with lymphoma (Clementi_2005, Cannella_2007). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hemophagocytic Lymphohistiocytosis. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Chia_2009). The following publications have been ascertained in the context of this evaluation (PMID: 17477373, 19487666, 15728124). ClinVar contains an entry for this variant (Variation ID: 639509). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic RCV003130039 SCV005411034 uncertain significance not provided 2024-02-15 criteria provided, single submitter clinical testing BS3_supporting
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City RCV000792321 SCV001469212 likely pathogenic Familial hemophagocytic lymphohistiocytosis 2 2020-05-06 no assertion criteria provided clinical testing

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