ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.464T>C (p.Met155Thr) (rs397516352)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036298 SCV000059950 likely pathogenic Primary dilated cardiomyopathy 2011-06-16 no assertion criteria provided clinical testing The Met155Thr variant has not been previously reported in the literature, but ha s been identified in 1 child with DCM and LVNC out of >1850 Caucasian probands tested by our laboratory. This low frequency is consistent with a pathogenic ro le. This child carried a second variant of unknown significance but the affected father carried the TNNI3 variant in isolation, supporting a pathogenic role. In addition, methionine (Met) at position 155 is conserved across mammals, frog, a nd zebrafish (though fruitfly and C. elegans carry a different amino acid), incr easing the likelihood that the change would not be tolerated. Computational anal yses are inconclusive with PolyPhen2 predicting pathogenic and AlignGVGD and SIF T predicting benign, though these models have not been validated sufficiently to determine pathogenicity. In summary, the overall evidence suggests that this va riant is likely pathogenic although we cannot fully exclude that is benign or pl ays a modifying role.

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