ClinVar Miner

Submissions for variant NM_001083116.3(PRF1):c.1183T>C (p.Cys395Arg)

dbSNP: rs2132475562
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002238590 SCV002511590 likely pathogenic Familial hemophagocytic lymphohistiocytosis 2022-04-19 criteria provided, single submitter clinical testing Variant summary: PRF1 c.1183T>C (p.Cys395Arg) results in a non-conservative amino acid change located in the Perforin-1, C2 domain (IPR037300) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248192 control chromosomes (gnomAD). c.1183T>C has been reported in the literature in at least homozygous individual affected with Familial Hemophagocytic Lymphohistiocytosis (Mhatre_2015). This data indicates that the variant may be associated with disease. Functional analysis on NK and Tc cells from the same homozygous patient showed that the perforin protein was not identifiable using anti-PRF1 antibodies (0% staining on both cell types) and NK cells had no cellular activity in vitro (0% cytotoxicity and granule release, Mhatre_2015). The cysteine residue at position 396 creates disulfide bridges with cysteines at position 381, therefore the substitution of Cysteine 395 is expected to alter protein structure and stability. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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