ClinVar Miner

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

dbSNP: rs776299562
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Total submissions: 5
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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.
Invitae 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)

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