Submissions for variant NM_001083116.3(PRF1):c.148G>A (p.Val50Met)

dbSNP: rs776299562

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000988377	SCV001138069	likely pathogenic	Familial hemophagocytic lymphohistiocytosis 2	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175585	SCV001339220	pathogenic	Familial hemophagocytic lymphohistiocytosis	2023-10-11	criteria provided, single submitter	clinical testing	Variant summary: PRF1 c.148G>A (p.Val50Met) results in a conservative amino acid change located in the membrane attack complex component/perforin (MACPF) domain (IPR020864) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 247726 control chromosomes (gnomAD). c.148G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Familial Hemophagocytic Lymphohistiocytosis (FHL), including a 4-month old infant, as well as in individuals with later disease onset (e.g. Goransdotter-Ericson_2001, Lee_2004, Horne_2008, Okur_2008, Chen_2017, Shabrish_2021). These data indicate that the variant is very likely to be associated with disease. The variant has also been reported in compound heterozygosity with a second pathogenic mutation in PRF1 in at least one individual who was not diagnosed with FHL, but experienced severe central nervous system/ neurological symptoms and was found to have imparied NK cell activity, suggesting an atypical disease presentation (Tesi_2015). Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal cytotoxic activity (e.g. Voskoboinik_2005, Risma_2006). The following publications have been ascertained in the context of this evaluation (PMID: 23592409, 29665027, 19487666, 11179007, 18710388, 14757862, 18190960, 16374518, 33746956, 23264592, 26184781, 17266056, 15755897, 24744671). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000988377	SCV001381665	pathogenic	Familial hemophagocytic lymphohistiocytosis 2	2023-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 50 of the PRF1 protein (p.Val50Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hemophagocytic lymphohistiocytosis (PMID: 11179007, 14757862, 18190960). 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: 802584). 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: 15755897, 16374518, 19487666). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001330251	SCV001521880	pathogenic	Aplastic anemia	2020-03-20	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. Both variants have been previously reported as disease-causing [PMID: 15755897, 19487666, 23592409, 11179007, ClinVar ID: 802584 for c.148G>A (p.V50M); PMID: 21959744, 23073290, 23592409, 11756153, 19487666, 21881043, 27577878, 15755897, 24916509, ClinVar ID: 520942 for c.445G>A (p.G149S)]
GeneDx	RCV001568143	SCV001791963	likely pathogenic	not provided	2020-03-03	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: impaired cytotoxic activity (Chia et al., 2009); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33365035, 32986178, 31130284, 32194620, 11179007, 29665027, 26184781, 18190960, 24744671, 14757862, 23592409, 19487666, 15755897, 16374518, 17873118)
Mayo Clinic Laboratories, Mayo Clinic	RCV001568143	SCV005413945	pathogenic	not provided	2024-02-14	criteria provided, single submitter	clinical testing	PM2, PM3_very_strong, PS3_supporting, PS4_moderate