Submissions for variant NM_001243133.2(NLRP3):c.1316C>T (p.Ala439Val)

dbSNP: rs121908146

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000214900	SCV000278944	pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that individuals with A441V have increased secretion of inflammatory cytokines, which correlates with disease severity (Rieber et al., 2015); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26115477, 22377911, 25596455, 26245507, 11687797, 26931528, 27134254, 28956000, 15801036, 31057541, 30568124, 31777803, 27535533, 19302049)
Invitae	RCV000701554	SCV000830359	pathogenic	Cryopyrin associated periodic syndrome	2023-09-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NLRP3 protein function. ClinVar contains an entry for this variant (Variation ID: 4370). This variant is also known as A439V or C1316T. This missense change has been observed in individuals with NLRP3-related disease (PMID: 11687797, 15801036, 25596455, 26245507, 26931528, 27134254). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 441 of the NLRP3 protein (p.Ala441Val).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000214900	SCV000885859	pathogenic	not provided	2022-11-23	criteria provided, single submitter	clinical testing	The NLRP3 c.1322C>T; p.Ala441Val variant (rs121908146), also known as Ala439Val, is published in the medical literature in several individuals and families with various autoinflammatory syndromes (Aoyama 2012, Hentgen 2005, Hoffman 2001, Houx 2015, Parker 2016) and is described as one of the more common pathogenic variants (Cuisset 2010). The variant is described as occurring de novo in at least one family (Hoffman 2001) and also has been shown to segregate with disease (Hoffman 2001, Hentgen 2005). The variant is reported in ClinVar (Variation ID: 4370), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 441 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.481). Considering available information, this variant is classified as pathogenic. References: Aoyama K et al. Cryopyrin-associated periodic syndrome: a case report and review of the Japanese literature. Acta Derm Venereol. 2012 Jul;92(4):395-8. PMID: 22377911. Cuisset L et al. Mutations in the autoinflammatory cryopyrin-associated periodic syndrome gene: epidemiological study and lessons from eight years of genetic analysis in France. Ann Rheum Dis. 2011 Mar;70(3):495-9. PMID: 21109514. Hentgen V et al. Intrafamilial variable phenotypic expression of a CIAS1 mutation: from Muckle-Wells to chronic infantile neurological cutaneous and articular syndrome. J Rheumatol. 2005 Apr;32(4):747-51. PMID: 15801036. PMID: 11687797. Hoffman HM et al. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet. 2001 Nov;29(3):301-5. PMID: 11687797. Houx L et al. Musculoskeletal symptoms in patients with cryopyrin-associated periodic syndromes: a large database study. Arthritis Rheumatol. 2015 Nov;67(11):3027-36. PMID: 26245507. Parker T et al. Neurology of the cryopyrin-associated periodic fever syndrome. Eur J Neurol. 2016 Jul;23(7):1145-51. PMID: 26931528.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262553	SCV002542594	pathogenic	Autoinflammatory syndrome	2021-01-06	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000004618	SCV002761654	likely pathogenic	Familial cold autoinflammatory syndrome 1	2023-07-26	criteria provided, single submitter	clinical testing	The NLRP3 c.1316C>T variant is classified as Likely Pathogenic (PS4_Moderate, PM2, PP1_Strong) The NLRP3 c.1316C>T variant (also known as p.Ala441Val) is a single nucleotide change in exon 3/9 of the NLRP3 gene, which is predicted to change the amino acid alanine at position 439 in the protein to valine. The variant has been reported in probands with a clinical presentation of Familial Cold Autoinflammatory Syndrome (PS4_Moderate). This variant is absent from population databases (PM2). Segregation with disease is noted within 2 large families, with 19 mutation positive individuals. (PP1_strong) (PubMed: 11687797, 27134254). The variant has been reported in dbSNP (rs121908146) and in the HGMD database: CM013248. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 4370).
Fulgent Genetics, Fulgent Genetics	RCV002476928	SCV002784124	pathogenic	Chronic infantile neurological, cutaneous and articular syndrome; Keratitis fugax hereditaria; Familial amyloid nephropathy with urticaria AND deafness; Familial cold autoinflammatory syndrome 1; Hearing loss, autosomal dominant 34, with or without inflammation	2021-07-29	criteria provided, single submitter	clinical testing
OMIM	RCV000004618	SCV000024792	pathogenic	Familial cold autoinflammatory syndrome 1	2001-11-01	no assertion criteria provided	literature only
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000004618	SCV000116318	not provided	Familial cold autoinflammatory syndrome 1		no assertion provided	not provided
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000214900	SCV001931798	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000214900	SCV001958584	pathogenic	not provided		no assertion criteria provided	clinical testing