Submissions for variant NM_144687.4(NLRP12):c.1854C>G (p.Tyr618Ter)

gnomAD frequency: 0.00013  dbSNP: rs142487599

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000729728	SCV000709825	uncertain significance	not provided	2021-06-01	criteria provided, single submitter	clinical testing	Observed in the homozygous state by exome sequencing in a child with Meckel-Gruber ciliopathy in published literature; the child had no evidence of inflammation, and variants associated with the presenting phenotype were excluded from the study (Shamia et al., 2015); Observed in the heterozygous state in an individual with familial cold autoinflammatory syndrome in published literature (Al-Mayouf SM et al., 2020); Nonsense variant predicted to result in protein truncation or nonsense mediated decay; This variant is associated with the following publications: (PMID: 31741047, 26141664, 27535533)
Invitae	RCV000685974	SCV000813477	uncertain significance	Familial cold autoinflammatory syndrome 2	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr618*) 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 (rs142487599, gnomAD 0.02%). 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: 503632). 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.
Eurofins Ntd Llc (ga)	RCV000729728	SCV000857414	uncertain significance	not provided	2017-10-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000729728	SCV001152057	uncertain significance	not provided	2019-03-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000685974	SCV001522056	uncertain significance	Familial cold autoinflammatory syndrome 2	2020-01-30	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic	RCV000729728	SCV002541664	uncertain significance	not provided	2021-12-20	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263820	SCV002542469	uncertain significance	Autoinflammatory syndrome	2021-09-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000685974	SCV003815950	uncertain significance	Familial cold autoinflammatory syndrome 2	2022-03-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003392443	SCV004119882	uncertain significance	NLRP12-related disorder	2022-12-13	criteria provided, single submitter	clinical testing	The NLRP12 c.1854C>G variant is predicted to result in premature protein termination (p.Tyr618*). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-54313059-G-C), which is rather high to be causative for an autosomal recessive disease. 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.
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000685974	SCV002011781	uncertain significance	Familial cold autoinflammatory syndrome 2	2021-08-25	no assertion criteria provided	clinical testing