Submissions for variant NM_144687.4(NLRP12):c.2499C>A (p.Asp833Glu)

gnomAD frequency: 0.00002  dbSNP: rs139956424

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000379617	SCV000414532	likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae	RCV000379617	SCV001396312	uncertain significance	Familial cold autoinflammatory syndrome 2	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 833 of the NLRP12 protein (p.Asp833Glu). This variant is present in population databases (rs139956424, gnomAD 0.003%). 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: 330018). 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263058	SCV002542510	uncertain significance	Autoinflammatory syndrome	2018-12-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002521246	SCV003759134	uncertain significance	Inborn genetic diseases	2022-11-17	criteria provided, single submitter	clinical testing	The c.2499C>A (p.D833E) alteration is located in exon 6 (coding exon 6) of the NLRP12 gene. This alteration results from a C to A substitution at nucleotide position 2499, causing the aspartic acid (D) at amino acid position 833 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.