Submissions for variant NM_001083116.3(PRF1):c.1090_1091del (p.Leu364fs)

gnomAD frequency: 0.00001  dbSNP: rs771552960

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000014724	SCV001579945	pathogenic	Familial hemophagocytic lymphohistiocytosis 2	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu364Glufs*93) in the PRF1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 192 amino acid(s) of the PRF1 protein. This variant is present in population databases (rs771552960, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with familial hemophagocytic lymphohistiocytosis (PMID: 11841437, 20015888, 23180437, 24578718, 26199792, 27896523, 29357941). ClinVar contains an entry for this variant (Variation ID: 13721). This variant disrupts a region of the PRF1 protein in which other variant(s) (p.Arg390*) have been determined to be pathogenic (PMID: 17601962, 21152410, 29357941). 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.
Baylor Genetics	RCV003473104	SCV004204190	pathogenic	Aplastic anemia	2024-03-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700236	SCV005203429	pathogenic	Familial hemophagocytic lymphohistiocytosis	2024-07-18	criteria provided, single submitter	clinical testing	Variant summary: PRF1 c.1090_1091delCT (p.Leu364GlufsX93) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein. The variant allele was found at a frequency of 1.2e-05 in 247068 control chromosomes. c.1090_1091delCT has been reported in the literature in multiple individuals affected with Familial Hemophagocytic Lymphohistiocytosis (examples: Hoshini_2020, Hori_2017). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 32914282, 27896523). ClinVar contains an entry for this variant (Variation ID: 13721). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005049338	SCV005679944	pathogenic	Aplastic anemia; Familial hemophagocytic lymphohistiocytosis 2; Lymphoma, non-Hodgkin, familial	2024-06-15	criteria provided, single submitter	clinical testing
OMIM	RCV000014724	SCV000034979	pathogenic	Familial hemophagocytic lymphohistiocytosis 2	2003-05-01	no assertion criteria provided	literature only
GeneReviews	RCV000014724	SCV001976570	not provided	Familial hemophagocytic lymphohistiocytosis 2		no assertion provided	literature only	Seen only in persons of Japanese descent [Trizzino et al 2008]