Submissions for variant NM_001083116.3(PRF1):c.724T>G (p.Cys242Gly)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800881	SCV005423153	uncertain significance	not specified	2024-10-16	criteria provided, single submitter	clinical testing	Variant summary: PRF1 c.724T>G (p.Cys242Gly) 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 was absent in 251232 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.724T>G has been reported in the literature in at least an individual affected with Familial Hemophagocytic Lymphohistiocytosis (example: Sato_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31789783). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005061449	SCV005698189	pathogenic	Familial hemophagocytic lymphohistiocytosis 2	2024-11-15	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 242 of the PRF1 protein (p.Cys242Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive familial hemophagocytic lymphohistiocytosis (PMID: 31789783; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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%. For these reasons, this variant has been classified as Pathogenic.