Submissions for variant NM_001083116.3(PRF1):c.1070G>A (p.Arg357Gln)

gnomAD frequency: 0.00027  dbSNP: rs140787739

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000820406	SCV000961117	uncertain significance	Familial hemophagocytic lymphohistiocytosis 2	2022-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 357 of the PRF1 protein (p.Arg357Gln). This variant is present in population databases (rs140787739, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with PRF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 662697). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV000820406	SCV001261254	uncertain significance	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002261229	SCV002542759	uncertain significance	Autoinflammatory syndrome	2021-12-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002478919	SCV002799707	uncertain significance	Aplastic anemia; Familial hemophagocytic lymphohistiocytosis 2; Lymphoma, non-Hodgkin, familial	2022-03-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002537468	SCV003633495	likely benign	Inborn genetic diseases	2022-05-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity	RCV003130075	SCV003809863	uncertain significance	not provided	2019-02-01	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV003130075	SCV005190799	uncertain significance	not provided		criteria provided, single submitter	not provided
Mayo Clinic Laboratories, Mayo Clinic	RCV003130075	SCV005411037	uncertain significance	not provided	2023-08-17	criteria provided, single submitter	clinical testing