ClinVar Miner

Submissions for variant NM_004895.4(NLRP3):c.598G>A (p.Val200Met) (rs121908147)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000224634 SCV000604557 likely benign not provided 2017-05-25 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000224634 SCV000891898 uncertain significance not provided 2018-09-30 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000509555 SCV000898853 uncertain significance Chronic infantile neurological, cutaneous and articular syndrome; Familial amyloid nephropathy with urticaria AND deafness; Familial cold urticaria 2018-06-08 criteria provided, single submitter clinical testing NLRP3 NM_004895.4 exon3 p.Val200Met (c.598G>A): This variant has been reported in the literature in the heterozygous and double heterozygous state in several individuals with clinical features consistent with NLRP3 related abnormal inflammatory response (e.g. Familial Cold Autoinflammatory Syndrome, Muckle-Wells syndrome) (Hoffman 2001 PMID:11687797, Aganna 2002 PMID:12355493, Loock 2010 PMID:20159265, Yuksel 2014 PMID:24135410, Kemmerle-Deschner 2015 PMID:26531310, Neocleous 2016 PMID: 27994174). In some reports, the variant also segregated in other family members with variable clinical features of disease. However, this variant is present in 2.4% (613/25766) of Finnish alleles, including 6 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs121908147). This variant is present in ClinVar with several discrepant classifications from "Benign to Variant of Uncertain Significance" (Variation ID:4371). This variant amino acid Methionine (Met) is present in several species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. Functional studies suggest that this variant will impact the protein NLRP3/cryopyrin inflammosome (Yuksel 2014 PMID:24135410); however, further studies are needed to understand its impact. Of note, at least 2 authors in the literature suggest that this variant may act as a risk allele or low penetrance variant (Aganna 2002 PMID:12355493, Yuksel 2014 PMID:24135410). In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224634 SCV000280952 likely benign not provided 2016-05-12 criteria provided, single submitter clinical testing Converted during submission to Likely benign.
GeneDx RCV000224634 SCV000490471 uncertain significance not provided 2018-12-10 criteria provided, single submitter clinical testing The V200M variant in the NLRP3 gene has been reported previously in association with cryopyrin-associated periodic syndromes (Hoffman et al., 2001; Aganna et al., 2002; Jesus et al., 2012; Kuemmerle-Deschner et al., 2015), as well as in healthy controls (Aganna et al., 2002; Aksentijevichet al., 2007). The variant is observed in 613/25766 (2.38%) alleles from individuals of European background in large population cohorts, including 7 homozygotes (Lek et al., 2016). The V200M 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. However, functional studies of the V200M variant shows that it results in increased interleukin-1ß secretions (Yüksel et al., 2014). Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a benign variant due to its high allele frequency in certain populations.
GenomeConnect, ClinGen RCV000509555 SCV000607138 not provided Chronic infantile neurological, cutaneous and articular syndrome; Familial amyloid nephropathy with urticaria AND deafness; Familial cold urticaria no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000004619 SCV000930272 likely benign Familial cold urticaria 2019-04-27 criteria provided, single submitter clinical testing
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000791008 SCV000930273 likely benign DEAFNESS, AUTOSOMAL DOMINANT 34, WITH OR WITHOUT INFLAMMATION 2019-04-27 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000312024 SCV000356923 likely benign Familial cold autoinflammatory syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000534651 SCV000646274 benign Cryopyrin associated periodic syndrome 2018-01-05 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000248492 SCV000966485 likely benign not specified 2018-02-10 criteria provided, single submitter clinical testing p.Val200Met in exon 5 of NLRP3: This variant (also reported as p.Val198Met) is n ot expected to have clinical significance because it has been identified in 0.85 % (2343/276948) of the total chromosomes in the Genome Aggregation Database incl uding 19 homozygotes. The highest allele frequency was 2.38% (613/25766) of Fin nish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broad institute.org; dbSNP rs121908147). The NLRP3 gene is associated with cryopyrin associated periodic syndrome (CAPS) which has an estimated prevalence of 1 in 36 0,000 (Orphanet, http://www.orpha.net, Orpha # 208650). While this variant has been reported in many individuals with features of CAPS and has been reported as a "low-penetrance allele", the variant was also identified in controls and unaf fected family members (Aggana 2002, Rowczenio 2013, Hoffman 2001, Look 2010, Lev y 2015). Furthermore, the frequency of the variant in the affected individuals in several studies was similar to the frequency of the variant in the Genome Agg regation Database (Kone-Paut 2007, Jesus 2012, Rowczenio 2013, Schuh 2015). One study found that in transfected embryonal kidney cells with the p.Val200Met var iant, IL-1? secretion was significantly increased compared to wild-type transfe cted cells (Yuksel 2014). However, another study found that patients with Val19 8Met and other variants described as low-penetrance alleles had similar response s as controls to inflammasome stimulation, compared with patients with clearly p athogenic NLRP3 variants (Rieber 2015). Furthermore, the valine (Val) residue a t position 200 is not conserved through species with >10 mammals having a methio nine (Met) at this position. In summary, due to the high frequency of the varia nt in the general population compared to the low estimated prevalence of CAPS, a nd the absence of enrichment of the variant in affected individuals, this varian t is likely benign. ACMG/AMP criteria applied: BS1, BS4, BP4.
OMIM RCV000004619 SCV000024793 pathogenic Familial cold urticaria 2001-11-01 no assertion criteria provided literature only
PreventionGenetics RCV000248492 SCV000310710 likely benign not specified criteria provided, single submitter clinical testing
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000004619 SCV000116361 not provided Familial cold urticaria no assertion provided not provided

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