Submissions for variant NM_001083116.3(PRF1):c.386G>C (p.Trp129Ser)

gnomAD frequency: 0.00007  dbSNP: rs768849283

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001779038	SCV002014977	pathogenic	Familial hemophagocytic lymphohistiocytosis	2021-10-19	criteria provided, single submitter	clinical testing	Variant summary: PRF1 c.386G>C (p.Trp129Ser) results in a non-conservative amino acid change located in the Membrane attack complex component/perforin (MACPF) domain (IPR020864) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251216 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PRF1 causing Familial Hemophagocytic Lymphohistiocytosis (6.8e-05 vs 0.0027), allowing no conclusion about variant significance. c.386G>C has been reported in the literature in multiple individuals affected with Familial Hemophagocytic Lymphohistiocytosis (example, Mhatre_2014, Sheth_2019, Yadav_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000663339	SCV002271413	pathogenic	Familial hemophagocytic lymphohistiocytosis 2	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 129 of the PRF1 protein (p.Trp129Ser). This variant is present in population databases (rs768849283, gnomAD 0.06%). This missense change has been observed in individual(s) with familial hemophagocytic lymphohistiocytosis (PMID: 22186995, 25577959, 30849948; Invitae). 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: 548929). 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. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000663339	SCV002768888	pathogenic	Familial hemophagocytic lymphohistiocytosis 2	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hemophagocytic lymphohistiocytosis, familial, 2 (HLH) (MIM#603553). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from tryptophan to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (17 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternative missense change at this position (p.Trp129Arg) has been reported in a heterozygous patient with HLH (PMID: 27209435). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic, and has been observed in multiple homozygous, compound heterozygous and a single heterozygous patient with HLH and perforin deficiency (ClinVar, PMID: 30849948, PMID: 24390453, PMID: 25577959, Kapoor (2016)). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000663339	SCV004046871	likely pathogenic	Familial hemophagocytic lymphohistiocytosis 2	2023-10-23	criteria provided, single submitter	clinical testing	This homozygous mis-sense variant is identified in a 2 month female with history of fever, lethargy, splenohepatomegaly, pancytopenia, raised ferritin, reduced fibrinogen. This nucleotide changeis present in gnomAD database with an allele frequency of 0.0068% [PM2]. To our knowledge there are no homozygotes in gnomAd database. Insilico prediction [REVEL: 0.7] predicts a deleterious nature of this variant [PP3]. A clinvar entry [Variation ID: 548929] for this variant is available with a “Pathogenic” interpretation by multiple submitter . PMID [30849948]. Based on the clinical correlation and available evidence, this variant is classified as "Likely Pathogenic"
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000663339	SCV004047220	likely pathogenic	Familial hemophagocytic lymphohistiocytosis 2		criteria provided, single submitter	clinical testing	The PRF1 c.386G>C variant has been reported in multiple individuals affected with Hemophagocytic lymphohistiocytosis, familial, 2 (Molleran et al., 2004; Mhatre et. al., 2014). The p.Trp129Ser variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.006767% in gnomAD database. This variant has been reported to the ClinVar database (Pathogenic/Likely Pathogenic). The amino acid Trp at position 129 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Trp129Ser in PRF1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Baylor Genetics	RCV003472061	SCV004204177	pathogenic	Aplastic anemia	2023-10-28	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000663339	SCV000778446	likely pathogenic	Familial hemophagocytic lymphohistiocytosis 2	2017-11-01	no assertion criteria provided	clinical testing	The observed variant c.386G>C(p.W129S) is not reported in 1000 Genomes and has a minor allele frequency of 0.00006618 in ExAc Database. The in silico prediction of the variant is Disease-causing by mutation taster and tolerated by SIFT and probably damaging by Polyphen-2.