ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.368C>T (p.Thr123Met) (rs397516345)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036285 SCV000059937 uncertain significance not specified 2013-03-06 criteria provided, single submitter clinical testing The Thr123Met variant in TNNI3 has not been reported in the literature, but has been identified by our laboratory in 1 adult with HCM and in 1 child with severe RVH (LMM unpublished data). This variant has not been identified in large and b road European American and African American populations by the NHLBI Exome Seque ncing Project (, though it may be common in oth er populations. Threonine (Thr) at position 123 is conserved in most mammals (ex cept squirrel and shrew), but not in more distantly related species, suggesting that a change at this position may be tolerated. Alternatively, this variant was predicted to be pathogenic using a computational tool clinically validated by o ur laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, additional studies are needed to fully as sess its clinical significance.
Color Health, Inc RCV001185542 SCV001351788 uncertain significance Cardiomyopathy 2019-12-13 criteria provided, single submitter clinical testing
Invitae RCV001219056 SCV001390976 uncertain significance Hypertrophic cardiomyopathy 2019-06-25 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 123 of the TNNI3 protein (p.Thr123Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs397516345, ExAC 0.01%). This variant has been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 43376). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). 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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