ClinVar Miner

Submissions for variant NM_004895.4(NLRP3):c.943A>G (p.Ile315Val) (rs180177501)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521236 SCV000616679 uncertain significance not provided 2018-12-05 criteria provided, single submitter clinical testing The I315V variant in the NLRP3 gene has been reported previously, using alternate nomenclature I313V, in association with CAPS in a French family, however, familial segregation information and additional clinical information were not included (Cuisset et al., 2011). The I315V variant is observed in 18/66420 (0.03%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). The I315V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species. However, I315V occurs in the NACHT domain, which is the major locus of CAPS-associated variants (Masters et al., 2009). In silico analysis predicts this variant likely does not alter the protein structure/function. We interpret I315V as a variant of uncertain significance.
Invitae RCV000525710 SCV000646279 uncertain significance Cryopyrin associated periodic syndrome 2019-09-11 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 315 of the NLRP3 protein (p.Ile315Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs180177501, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with systemic auto-inflammatory disease and cryopyrin-associated periodic syndrome (PMID: 26386126, 27191192) and it has been reported to segregate with cryopyrin-associated periodic syndrome in one family (PMID: 21109514). This variant is also known as p.Ile313Val in the literature. ClinVar contains an entry for this variant (Variation ID: 97989). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine, Partners HealthCare 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 Clinical Services Laboratory,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 Clinical Services Laboratory,Illumina RCV000084252 SCV001256531 benign Familial cold urticaria 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 Clinical Services Laboratory,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.
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000084252 SCV000116388 not provided Familial cold urticaria no assertion provided not provided

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