Submissions for variant NM_144687.4(NLRP12):c.2575C>T (p.Arg859Trp)

gnomAD frequency: 0.00009  dbSNP: rs573629753

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000823537	SCV000414531	benign	Familial cold autoinflammatory syndrome 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV000823537	SCV000964398	uncertain significance	Familial cold autoinflammatory syndrome 2	2023-12-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 859 of the NLRP12 protein (p.Arg859Trp). This variant is present in population databases (rs573629753, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with NLRP12-related conditions. ClinVar contains an entry for this variant (Variation ID: 330017). 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) performed at Invitae indicates that this missense variant is not expected to disrupt NLRP12 protein function with a negative predictive value of 80%. 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.
GeneDx	RCV001548731	SCV001768694	uncertain significance	not provided	2021-06-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533)
New York Genome Center	RCV000823537	SCV002099212	uncertain significance	Familial cold autoinflammatory syndrome 2	2021-03-26	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263057	SCV002542512	uncertain significance	Autoinflammatory syndrome	2019-03-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002521245	SCV003692202	uncertain significance	Inborn genetic diseases	2021-07-06	criteria provided, single submitter	clinical testing	The c.2575C>T (p.R859W) alteration is located in exon 6 (coding exon 6) of the NLRP12 gene. This alteration results from a C to T substitution at nucleotide position 2575, causing the arginine (R) at amino acid position 859 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.