Submissions for variant NM_001083116.3(PRF1):c.755A>G (p.Asn252Ser)

gnomAD frequency: 0.00756  dbSNP: rs28933375

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000246747	SCV000306479	likely benign	not specified		criteria provided, single submitter	clinical testing
GeneDx	RCV000767055	SCV000617802	likely benign	not provided	2022-02-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15728124, 18198357, 18496551, 22995991, 24309606, 20981092, 23592409, 25569260, 27153395, 29146883, 32659967, 32356861, 32198610, 32098966, 10583959, 34938098, 15459303, 15659737, 15755897)
Invitae	RCV000014716	SCV000644893	benign	Familial hemophagocytic lymphohistiocytosis 2	2024-02-01	criteria provided, single submitter	clinical testing
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV000246747	SCV000864329	likely benign	not specified	2017-08-14	criteria provided, single submitter	clinical testing	BS1, BS4, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, is a variant that did not show segregation with affected members of a family (PMID: 15659737), and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory).
Illumina Laboratory Services, Illumina	RCV000014716	SCV001264277	benign	Familial hemophagocytic lymphohistiocytosis 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000767055	SCV001448797	likely benign	not provided	2019-08-06	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000767055	SCV002011175	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000246747	SCV002069986	benign	not specified	2021-04-19	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002260965	SCV002542796	benign	Autoinflammatory syndrome	2021-07-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000246747	SCV002555969	benign	not specified	2022-06-17	criteria provided, single submitter	clinical testing	Variant summary: PRF1 c.755A>G (p.Asn252Ser) results in a 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 0.005 in 282834 control chromosomes in the gnomAD database, including 9 homozygotes; occuring predominantly at a frequency of 0.0087 within the African or African-American subpopulation in the gnomAD database, with 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in PRF1 causing Familial Hemophagocytic Lymphohistiocytosis phenotype (0.0027), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Seven ClinVar submitters have assessed the variant since 2014: one classified the variant as of uncertain significance, three as likely benign, and three as benign. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000767055	SCV004126688	likely benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	PRF1: BP4, BS2
OMIM	RCV000014716	SCV000034971	uncertain significance	Familial hemophagocytic lymphohistiocytosis 2	2005-06-01	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000246747	SCV001932624	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000767055	SCV001953961	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000767055	SCV001966837	likely benign	not provided		no assertion criteria provided	clinical testing