ClinVar Miner

Submissions for variant NM_001083116.3(PRF1):c.1620A>G (p.Gln540=)

gnomAD frequency: 0.00083  dbSNP: rs149776121
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000887811 SCV001031397 benign Familial hemophagocytic lymphohistiocytosis 2 2024-01-31 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000887811 SCV001260918 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV001358428 SCV002009737 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV002264049 SCV002542354 uncertain significance Autoinflammatory syndrome 2020-05-01 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001358428 SCV004126686 likely benign not provided 2022-10-01 criteria provided, single submitter clinical testing PRF1: BP4, BP7
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001358428 SCV001554157 uncertain significance not provided no assertion criteria provided clinical testing The PRF1 p.Gln540Gln variant was identified in one homozygous individual with multiple sclerosis and one heterozygous individual with familial hemophagocytic lymphohistiocytosis (Cappellano_2008_PMID:18496551, Liu_2015_PMID:26274329). The variant was identified in dbSNP (ID: rs149776121), ClinVar (classified as benign by Invitae) and LOVD 3.0 (variant effect not shared), but was not identified in Cosmic. The variant was identified in control databases in 499 of 268182 chromosomes (1 homozygous) at a frequency of 0.001861 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: East Asian in 245 of 19248 chromosomes (freq: 0.01273), European (Finnish) in 81 of 25022 chromosomes (freq: 0.003237), South Asian in 76 of 30526 chromosomes (freq: 0.00249), Other in 11 of 6702 chromosomes (freq: 0.001641), European (non-Finnish) in 76 of 118130 chromosomes (freq: 0.000643), Latino in 6 of 35106 chromosomes (freq: 0.000171), African in 3 of 23586 chromosomes (freq: 0.000127) and Ashkenazi Jewish in 1 of 9862 chromosomes (freq: 0.000101). The p.Gln540Gln variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. However, 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the creation of a new 3' splice site. However, this has not been confirmed by RNA analysis and is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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