ClinVar Miner

Submissions for variant NM_004895.4(NLRP3):c.1303A>G (p.Thr435Ala) (rs876661016)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000215068 SCV000279200 uncertain significance not provided 2015-11-13 criteria provided, single submitter clinical testing To our knowledge, the T435A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant. The T435A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. It is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position conserved in mammals. However, in-silico analysis predicts this variant likely does not alter the protein structure/function. Missense variants at the same codon (T435I) and in nearby residues (K437E, T438P/A/N/I) have been reported in the Human Gene Mutation Database in association with NLRP3-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

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