Submissions for variant NM_001083116.3(PRF1):c.1130G>A (p.Cys377Tyr)

dbSNP: rs2493483298

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV003231693	SCV003929668	uncertain significance	not provided	2024-12-23	criteria provided, single submitter	clinical testing	Identified in patients with hemophagocytic lymphohistiocytosis in the published literature who harbored a second PRF1 variant, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 31934312, 29152263, 30104219); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30104219, 31934312, 29152263)
Baylor Genetics	RCV004572887	SCV005052450	likely pathogenic	Aplastic anemia	2024-03-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV005102461	SCV005815815	pathogenic	Familial hemophagocytic lymphohistiocytosis 2	2025-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 377 of the PRF1 protein (p.Cys377Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hemophagocytic lymphohistiocytosis (PMID: 30104219; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2504233). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005240732	SCV005884060	uncertain significance	not specified	2024-12-27	criteria provided, single submitter	clinical testing	Variant summary: PRF1 c.1130G>A (p.Cys377Tyr) results in a non-conservative amino acid change in 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 245414 control chromosomes (gnomAD). c.1130G>A has been reported in the literature in individuals affected with Familial Hemophagocytic Lymphohistiocytosis (Benezech_2017, Lucchini_2018). 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. The following publications have been ascertained in the context of this evaluation (PMID: 30104219, 29152263). ClinVar contains an entry for this variant (Variation ID: 2504233). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.