Submissions for variant NM_144687.4(NLRP12):c.1054C>T (p.Arg352Cys)

gnomAD frequency: 0.00019  dbSNP: rs199881207

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000627081	SCV000835067	likely benign	Familial cold autoinflammatory syndrome 2	2023-12-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000627081	SCV001158137	uncertain significance	Familial cold autoinflammatory syndrome 2	2019-09-27	criteria provided, single submitter	clinical testing	The NLRP12 c.1054C>T; p.Arg352Cys variant (rs199881207) is published in the medical literature in 3 unrelated individuals with periodic fever or autoimmune disease without urticaria (Jeru 2011, Rusmini 2016). The variant is reported in the ClinVar database (Variation ID: 523654) and in the general population with an allele frequency of 0.04% (102/282638 alleles) in the Genome Aggregation Database. The arginine at this position is moderately conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Experiments in cell culture show this variant did not affect the NF-KB inhibitory activity, but did enhance processing of caspase-1 compared to wild type (Jeru 2011); these authors suggested that this variant may act in a gain of function mechanism, in contrast to NLRP12 nonsense variants that appear to have a loss of function. However, given the limited clinical and functional data, the significance of the variant is uncertain at this time. References: Jeru I et al. Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes. Arthritis Rheum. 2011 May;63(5):1459-64. Rusmini M et al. Next-generation sequencing and its initial applications for molecular diagnosis of systemic auto-inflammatory diseases. Ann Rheum Dis. 2016 Aug;75(8):1550-7.
CeGaT Center for Human Genetics Tuebingen	RCV001311905	SCV001502271	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	NLRP12: BP4
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263840	SCV002542434	likely benign	Autoinflammatory syndrome	2020-02-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000627081	SCV002759339	uncertain significance	Familial cold autoinflammatory syndrome 2	2022-12-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000627081	SCV004805612	likely benign	Familial cold autoinflammatory syndrome 2	2024-03-25	criteria provided, single submitter	research
OMIM	RCV000627081	SCV000747891	pathogenic	Familial cold autoinflammatory syndrome 2	2023-04-18	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001311905	SCV001740400	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001311905	SCV001965612	uncertain significance	not provided		no assertion criteria provided	clinical testing