Submissions for variant NM_144687.4(NLRP12):c.3046C>T (p.Arg1016Ter)

gnomAD frequency: 0.00470  dbSNP: rs35064500

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001080137	SCV000414512	likely benign	Familial cold autoinflammatory syndrome 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Invitae	RCV001080137	SCV000767406	likely benign	Familial cold autoinflammatory syndrome 2	2024-01-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000645655	SCV001152052	uncertain significance	not provided	2018-11-01	criteria provided, single submitter	clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001080137	SCV001984643	uncertain significance	Familial cold autoinflammatory syndrome 2	2020-09-06	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263050	SCV002542540	benign	Autoinflammatory syndrome	2022-04-13	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001080137	SCV004563234	uncertain significance	Familial cold autoinflammatory syndrome 2	2023-09-08	criteria provided, single submitter	clinical testing	The NLRP12 c.3046C>T; p.Arg1016Ter variant (rs35064500) is present in the African population with an allele frequency of 1.6% (401/24,956 alleles including 3 homozygotes) in the Genome Aggregation Database. To our knowledge, the variant has not been reported in any individuals with familial cold autoinflammatory syndrome, but has been reported in individuals with unrelated or non-specific conditions (Modi 2017, Ung 2017, Glicksberg 2019, El Naofal 2023) and is listed in the ClinVar Database (Variation ID: 330001). This variant results in a premature termination codon in the penultimate exon of the NLRP12 gene and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Although the allele frequency of this variant may be incompatible with autosomal dominant familial autoinflammatory syndrome, given the lack of clinical and functional data, the significance of the p.Arg1016Ter variant is uncertain at this time. References: El Naofal M et al. The genomic landscape of rare disorders in the Middle East. Genome Med. 2023 Jan 27;15(1):5. PMID: 36703223 Glicksberg BS et al. Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits. BMC Med Genomics. 2019 Jul 25;12(Suppl 6):108. PMID: 31345219 Modi BP et al. Mutations in fetal genes involved in innate immunity and host defense against microbes increase risk of preterm premature rupture of membranes (PPROM). Mol Genet Genomic Med. 2017 Nov;5(6):720-729. Ung C et al. Whole exome sequencing identification of novel candidate genes in patients with proliferative diabetic retinopathy. Vision Res. 2017 Oct;139:168-176.
PreventionGenetics, part of Exact Sciences	RCV003910268	SCV004721942	likely benign	NLRP12-related disorder	2020-01-06	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001778921	SCV002014775	risk factor	Multisystem inflammatory syndrome in children	2021-11-14	no assertion criteria provided	research