Submissions for variant NM_001243133.2(NLRP3):c.674C>T (p.Ala225Val)

gnomAD frequency: 0.00019  dbSNP: rs180177493

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000217712	SCV000278936	uncertain significance	not provided	2018-06-07	criteria provided, single submitter	clinical testing	The A227V variant has been reported, using alternative nomenclature, in an individual with rheumatoid arthritis, high leukocyte count and recurrent fever (Verma et al., 2008). The variant is observed in 53/25786 (0.2055%) alleles from individuals of Finnish background in large population cohorts (Lek et al., 2016). The variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. However, the variant is located in the NACHT domain, which is the major locus of CAPS-associated pathogenic variants (Masters et al., 2009). In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001078842	SCV000767332	likely benign	Cryopyrin associated periodic syndrome	2024-04-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000084227	SCV001520736	uncertain significance	Familial cold autoinflammatory syndrome 1	2019-03-14	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262695	SCV002542641	uncertain significance	Autoinflammatory syndrome	2020-07-01	criteria provided, single submitter	clinical testing
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000084227	SCV000116362	not provided	Familial cold autoinflammatory syndrome 1		no assertion provided	not provided
PreventionGenetics, part of Exact Sciences	RCV004529880	SCV004727022	likely benign	NLRP3-related disorder	2024-06-21	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).