Submissions for variant NM_144687.4(NLRP12):c.1022C>T (p.Thr341Ile)

gnomAD frequency: 0.00019  dbSNP: rs200996095

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000802476	SCV000942309	uncertain significance	Familial cold autoinflammatory syndrome 2	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 341 of the NLRP12 protein (p.Thr341Ile). This variant is present in population databases (rs200996095, gnomAD 0.04%), including at least one homozygous and/or hemizygous individual. 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: 647864). 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 expected to disrupt NLRP12 protein function with a positive 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.
Illumina Laboratory Services, Illumina	RCV000802476	SCV001290829	benign	Familial cold autoinflammatory syndrome 2	2018-01-12	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.
CeGaT Center for Human Genetics Tuebingen	RCV001815479	SCV002063815	uncertain significance	not provided	2024-05-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000802476	SCV003799241	uncertain significance	Familial cold autoinflammatory syndrome 2	2022-11-23	criteria provided, single submitter	clinical testing	The NLRP12 c.1022C>T; p.Thr341Ile variant (rs200996095), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 647864). This variant is found in the general population with an overall allele frequency of 0.02% (58/282590 alleles) in the Genome Aggregation Database. The threonine at codon 341 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.902). Due to limited information, the clinical significance of this variant is uncertain at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702432	SCV005204938	uncertain significance	not specified	2024-06-10	criteria provided, single submitter	clinical testing	Variant summary: NLRP12 c.1022C>T (p.Thr341Ile) results in a non-conservative amino acid change located in the DAPIN domain (IPR004020) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 251192 control chromosomes, predominantly at a frequency of 0.00042 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in NLRP12 causing Familial Cold Autoinflammatory Syndrome 2, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1022C>T in individuals affected with Familial Cold Autoinflammatory Syndrome 2 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 647864). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004751715	SCV005353865	uncertain significance	NLRP12-related disorder	2024-07-05	no assertion criteria provided	clinical testing	The NLRP12 c.1022C>T variant is predicted to result in the amino acid substitution p.Thr341Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.041% of alleles in individuals, including one homozygous individual, of European (Non-Finnish) descent in gnomAD. This variant has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/647864/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.