ClinVar Miner

Submissions for variant NM_004895.4(NLRP3):c.2861C>T (p.Thr954Met) (rs139814109)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756443 SCV000884261 uncertain significance not provided 2017-08-20 criteria provided, single submitter clinical testing The NLRP3 c.2861C>T;p.Thr954Met variant has been reported in at least two individuals with suspected familial cold-induced inflammatory syndrome or cryopyrin associated periodic syndrome (Gonzalez-Roca 2013, Savostyanov 2014). The variant is listed in the ClinVar database (Variation ID: 234293) and the dbSNP variant database (rs139814109) with an allele frequency of up to 0.1047 percent (9/8591 alleles) in the European American population in the Exome Variant Server and up to 0.3866 percent (119/30782 alleles, 1 homozygote) in the South Asian population in the Genome Aggregation Database. The amino acid at this position is highly conserved and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, there is insufficient evidence to classify this variant with certainty. Pathogenic NLRP3 variants are causative for CINCA syndrome, familial cold-induced inflammatory syndrome, and Muckle-Wells syndrome (OMIM#606416). References: 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.
GeneDx RCV000220345 SCV000278951 uncertain significance not specified 2016-11-03 criteria provided, single submitter clinical testing The T954M variant in the NLRP3 has been reported previously in patients with autoimmune disorder with limited evidence for pathogenicity (Arts et al., 2015; Mian et al., 2015). It was not observed with a significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. T954M is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Although this substitution occurs at a position where amino acids with similar properties to Threonine are tolerated across species, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether T954M is a disease-causing variant or a rare benign variant.
Illumina Clinical Services Laboratory,Illumina RCV000353278 SCV000357004 likely benign Chronic infantile neurological, cutaneous and articular syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000277197 SCV000357005 likely benign Familial cold autoinflammatory syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000313549 SCV000357006 likely benign Familial amyloid nephropathy with urticaria AND deafness 2016-06-14 criteria provided, single submitter clinical testing

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