Submissions for variant NM_001083116.3(PRF1):c.1349C>T (p.Thr450Met)

gnomAD frequency: 0.00003  dbSNP: rs189650890

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000547072	SCV000644878	pathogenic	Familial hemophagocytic lymphohistiocytosis 2	2024-02-19	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 450 of the PRF1 protein (p.Thr450Met). This variant is present in population databases (rs189650890, gnomAD 0.01%). This missense change has been observed in individual(s) with familial hemophagocytic lymphohistiocytosis (PMID: 15632205, 15728124, 17266056, 18074390, 20092789, 21152410, 21881043, 25233452, 25297583, 26903364). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 468301). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PRF1 protein function. Experimental studies have shown that this missense change affects PRF1 function (PMID: 15632205, 19487666). For these reasons, this variant has been classified as Pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000547072	SCV000993625	pathogenic	Familial hemophagocytic lymphohistiocytosis 2	2019-03-26	criteria provided, single submitter	research
Revvity Omics, Revvity	RCV001783053	SCV002024742	likely pathogenic	not provided	2019-01-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003476292	SCV004204180	pathogenic	Aplastic anemia	2024-02-21	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000547072	SCV004808173	pathogenic	Familial hemophagocytic lymphohistiocytosis 2	2024-03-29	criteria provided, single submitter	clinical testing
Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	RCV000547072	SCV005873656	likely pathogenic	Familial hemophagocytic lymphohistiocytosis 2	2020-08-23	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005398810	SCV006057923	pathogenic	Aplastic anemia; Familial hemophagocytic lymphohistiocytosis 2; Lymphoma, non-Hodgkin, familial	2023-01-16	criteria provided, single submitter	research