Submissions for variant NM_001243133.2(NLRP3):c.937A>G (p.Ile313Val)

gnomAD frequency: 0.00025  dbSNP: rs180177501

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521236	SCV000616679	uncertain significance	not provided	2022-01-12	criteria provided, single submitter	clinical testing	Identified in additional patients with suspected CAPS or systemic auto-inflammatory disorders in published literature, although detailed clinical information is not available (Cuisset et al., 2011; Rusmini et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as p.(I313V); This variant is associated with the following publications: (PMID: 32082075, 32199921, 34426522, 28814775, 19302049, 21109514, 26386126, 27191192)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000525710	SCV000646279	likely benign	Cryopyrin associated periodic syndrome	2023-12-28	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825406	SCV000966703	uncertain significance	not specified	2018-09-13	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Ile315Val var iant in NLRP3 has been reported (as p.Ile313Val) in 1 individual with CAPS, and segregated with disease in at least 3 affected family members (Cuisset 2011). It was also reported in one individual with mevalonate kinase deficiency who carri ed additional variants in the MKV gene that were sufficient to explain their phe notype (Rusmini 2016). This variant has also been identified in 0.05% (58/126272 ) of European chromosomes by the Genome Aggregation Database (gnomAD; http://gno mad.broadinstitute.org/). Computational prediction tools and conservation analys is suggest that an isoleucine to valine change at position 315 may not impact th e protein, though this information is not predictive enough to rule out pathogen icity. On the other hand, additional computational tools suggest that this varia nt may create a novel splice site; however, this prediction may not reflect biol ogical function. In summary, while its frequency suggests that it is more likely to be benign, the clinical significance of the p.Ile315Val variant is uncertain due to the presence of conflicting data. ACMG/AMP Criteria applied: BS1, PP1.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000825406	SCV001158389	uncertain significance	not specified	2019-05-09	criteria provided, single submitter	clinical testing	The NLRP3 c.943A>G; p.Ile315Val variant (rs180177501) is reported in the medical literature in individuals with cryopyrin-associated periodic syndrome and segregating with disease in at least one family (Cuisset 2011, Rusmini 2016). The variant is reported in the ClinVar database as a variant of uncertain significance (Variation ID: 97989) and an expert panel considers this variant to be of uncertain significance (Van Gijn 2018). The variant is reported in the European (non-Finnish population) with an allele frequency of 0.05% (61/128760 alleles) in the Genome Aggregation Database. The isoleucine at this position is moderately conserved and computational algorithms (PolyPhen-2, SIFT) predicts this variant is tolerated. However, most known pathogenic NLRP3 variants occur in this region (Masters 2009). Given the lack of clinical and functional data, the significance of the variant is uncertain at this time. References: 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. Masters SL et al. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease (*).Annu Rev Immunol. 2009;27:621-68. 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. Van Gijn ME et al. New workflow for classification of genetic variants' pathogenicity applied to hereditary recurrent fevers by the International Study Group for Systemic Autoinflammatory Diseases (INSAID). J Med Genet. 2018 Aug;55(8):530-537.
Illumina Laboratory Services, Illumina	RCV001100031	SCV001256530	benign	Chronic infantile neurological, cutaneous and articular syndrome	2017-04-28	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV000084252	SCV001256531	benign	Familial cold autoinflammatory syndrome 1	2017-04-28	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001102016	SCV001258664	benign	Familial amyloid nephropathy with urticaria AND deafness	2017-04-28	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262699	SCV002542650	uncertain significance	Autoinflammatory syndrome	2021-01-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002513894	SCV003720009	uncertain significance	Inborn genetic diseases	2021-04-17	criteria provided, single submitter	clinical testing	The c.943A>G (p.I315V) alteration is located in exon 3 (coding exon 3) of the NLRP3 gene. This alteration results from a A to G substitution at nucleotide position 943, causing the isoleucine (I) at amino acid position 315 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000084252	SCV000116388	not provided	Familial cold autoinflammatory syndrome 1		no assertion provided	not provided
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000521236	SCV001741235	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000521236	SCV001931188	uncertain significance	not provided		no assertion criteria provided	clinical testing