Submissions for variant NM_144687.4(NLRP12):c.850C>T (p.Arg284Ter)

gnomAD frequency: 0.00044  dbSNP: rs104895564

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000001663	SCV000951288	uncertain significance	Familial cold autoinflammatory syndrome 2	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg284*) in the NLRP12 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in NLRP12 cause disease. This variant is present in population databases (rs104895564, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with clinical features of familial cold autoinflammatory syndrome (FCAS) (PMID: 18230725). ClinVar contains an entry for this variant (Variation ID: 1596). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NLRP12 function (PMID: 18230725, 21360512). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000001663	SCV001474498	uncertain significance	Familial cold autoinflammatory syndrome 2	2019-09-21	criteria provided, single submitter	clinical testing	The NLRP12 c.850C>T; p.Arg284Ter variant (rs104895564) is published in the medical literature in one family with a hereditary periodic fever syndrome (Jeru 2008, Jeru 2011), but has also been reported in a reportedly unaffected individual (Rodriguez-Flores 2014). The variant is reported in the ClinVar database (Variation ID: 1596) and in the African population with an allele frequency of 0.1% (34/24916 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Functional studies have shown conflicting NFKB activation by this variant (Borghini 2011, Jeru 2008). Although the physiological relevance of NLRP12 in periodic fever syndrome is certain, if disease is caused by loss-of-function variants remained to be determined (Tuncer 2014). Due to conflicting information, the clinical significance of this variant is uncertain. References: Borghini S et al. Clinical presentation and pathogenesis of cold-induced autoinflammatory disease in a family with recurrence of an NLRP12 mutation. Arthritis Rheum. 2011 Mar;63(3):830-9. Jeru I et al. Mutations in NALP12 cause hereditary periodic fever syndromes. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1614-9. Jeru I et al. Role of interleukin-1ß in NLRP12-associated autoinflammatory disorders and resistance to anti-interleukin-1 therapy. Arthritis Rheum. 2011 Jul;63(7):2142-8. Rodriguez-Flores JL et al. Exome sequencing identifies potential risk variants for Mendelian disorders at high prevalence in Qatar. Hum Mutat. 2014 Jan;35(1):105-16. Tuncer S et al. The multifaceted nature of NLRP12. J Leukoc Biol. 2014 Dec;96(6):991-1000.
New York Genome Center	RCV000001663	SCV002097825	uncertain significance	Familial cold autoinflammatory syndrome 2	2021-02-05	criteria provided, single submitter	clinical testing	The inherited c.850C>T(p.Arg284Ter)stop-gained variant identified in exon 3(of 10) of the NLRP12 gene creates a premature translation termination codon and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. However, loss-of-function is not an established mechanism of disease for NLRP12 related disorder. The p.Arg284Ter variant has 0.0004403 allele frequency in the gnomAD(v3) database across all populations represented in the database (67 out of 152,152 heterozygous alleles, no homozygotes), and 0.001448 allele frequency in the African/African-American sub-population (60 out of 41,450 heterozygous alleles, no homozygotes). Although the variant has been reported in a family affected with hereditary periodic fever syndrome [PMID: 18230725], functional studies show contradictory data regarding potential pathogenicity of this variant [PMID: 18230725; PMID: 21360512]. Given the lack of compelling evidence for its pathogenicity, the inherited c.850C>T(p.Arg284Ter) stop-gained variant identified in the NLRP12geneis reported as a variant of uncertain significance.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262535	SCV002542570	uncertain significance	Autoinflammatory syndrome	2019-08-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000001663	SCV002783500	uncertain significance	Familial cold autoinflammatory syndrome 2	2022-04-05	criteria provided, single submitter	clinical testing
OMIM	RCV000001663	SCV000021819	pathogenic	Familial cold autoinflammatory syndrome 2	2008-02-05	flagged submission	literature only
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000084149	SCV000116280	not provided	not provided		no assertion provided	not provided
GeneDx	RCV000084149	SCV003195117	pathogenic	not provided	2023-02-07	flagged submission	clinical testing	Reported in association with NLRP12-related familial cold autoinflammatory syndrome in the published literature (Jeru et al., 2008); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect (Jeru et al., 2008); This variant is associated with the following publications: (PMID: 34054914, 25525159, 21480187, 31589614, 30788684, 32743516, 33525590, 30559449, 24906912, 31820221, 28421071, 27314497, 24123366, 20007570, 21360512, 18230725)