ClinVar Miner

Submissions for variant NM_006440.5(TXNRD2):c.745C>T (p.Arg249Cys) (rs557142042)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000426060 SCV000533673 uncertain significance not provided 2016-11-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TXNRD2 gene. The R249C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R249C variant 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 that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.
Invitae RCV000686162 SCV000813666 uncertain significance Primary dilated cardiomyopathy 2020-09-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 249 of the TXNRD2 protein (p.Arg249Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs557142042, ExAC 0.9%). This variant has not been reported in the literature in individuals with TXNRD2-related disease. ClinVar contains an entry for this variant (Variation ID: 390757). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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