Submissions for variant NM_001243133.2(NLRP3):c.2855C>T (p.Thr952Met)

gnomAD frequency: 0.00051  dbSNP: rs139814109

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001705232	SCV000278951	benign	not provided	2019-11-05	criteria provided, single submitter	clinical testing	Reported previously in patients with autoimmune disorder with limited evidence for pathogenicity (Arts et al., 2015; Mian et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25639832, 27943240, 25979514)
Illumina Laboratory Services, Illumina	RCV000353278	SCV000357004	likely benign	Chronic infantile neurological, cutaneous and articular syndrome	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.
Illumina Laboratory Services, Illumina	RCV000277197	SCV000357005	likely benign	Familial cold autoinflammatory syndrome 1	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.
Illumina Laboratory Services, Illumina	RCV000313549	SCV000357006	likely benign	Familial amyloid nephropathy with urticaria AND deafness	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001705232	SCV000884261	uncertain significance	not provided	2021-03-16	criteria provided, single submitter	clinical testing	The NLRP3 c.2861C>T; p.Thr954Met variant (rs139814109) is reported in the literature in at least two individuals with suspected familial cold-induced inflammatory syndrome or cryopyrin associated periodic syndrome (Gonzalez-Roca 2013, Savostyanov 2014), but did not segregate with disease in a family with autoimmune disorders (Arts 2015). The p.Thr954Met variant is listed in ClinVar (Variation ID: 234293), and is found in the general population with an overall allele frequency of 0.12% (339/282814 alleles, including a single homozygote) in the Genome Aggregation Database. The threonine at codon 954 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.223). However, given the lack of clinical and functional data, the significance of the p.Thr954Met variant is uncertain at this time. References: Arts P et al. A missense mutation underlies defective SOCS4 function in a family with autoimmunity. J Intern Med. 2015 Aug;278(2):203-10. Gonzalez-Roca E et al. P02-021 Atypical CAPS consequence of novel NLPR3 mutations. Pediatric Rheumatology 2013; 11(Suppl):A128. Savostyanov K et al. AB0888 Mutations in TNFRSF1A and NLRP3 Genes in Patients with Recurrent Inflammatory Attacks in Russian Population. Ann Rheum Dis 2014; 73(2 Suppl):1094-5.
Invitae	RCV001082685	SCV001012796	likely benign	Cryopyrin associated periodic syndrome	2024-01-16	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000220345	SCV001652931	likely benign	not specified	2020-08-14	criteria provided, single submitter	clinical testing	The p.Thr954Met variant in NLRP3 is classified as likely benign because although it has been reported in several individuals with cryopyrin-associated period syndromes and one individual with syndromic pyoderma gangrenosum (Gonzalez-Roca 2013, Arts 2015 PMID 25639832 , Marzano 2017 PMID 27943240, Martorana 2017 PMID 28421071 , Gaggiano 2019 PMID 32082075, Bozgeyik 2020 PMID 32199921), it has been identified in 0.39% (120/30616) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org), which is a frequency that is too high to be consistent with being causative for the disorder. ACMG/AMP Criteria applied: BS1, BP4.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262815	SCV002543678	likely benign	Autoinflammatory syndrome	2021-01-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532812	SCV004750283	likely benign	NLRP3-related disorder	2022-03-28	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).