Submissions for variant NM_001083116.3(PRF1):c.539+2T>A

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV003472526	SCV004204199	likely pathogenic	Aplastic anemia	2023-09-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003626869	SCV004405958	pathogenic	Familial hemophagocytic lymphohistiocytosis 2	2024-10-14	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 2 of the PRF1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PRF1-related conditions. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the PRF1 protein in which other variant(s) (p.Gln446Pro) have been determined to be pathogenic (PMID: 25326637, 26450956). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.