ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.493G>T (p.Glu165Ter) (rs1057521530)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000422803 SCV000523442 likely pathogenic not provided 2016-01-15 criteria provided, single submitter clinical testing The likely pathogenic E165X variant in the TNNI3 gene has not been reported as a pathogenic variant or 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. E165X is predicted to cause loss of normal protein function by protein truncation (loss of the last 46 amino acids). However, no nonsense variants in the TNNI3 gene have been reported in HGMD (Stenson et al., 2014). Most of the pathogenic variants in TNNI3 reported in HGMD are missense substitutions that affect the calcium sensitivity of contraction. While haploinsufficiency is not a well-established mechanism of disease for the TNNI3 gene, other truncation variants have been reported in HGMD (Stenson et al., 2014). Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, additional data is required.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000422803 SCV001152075 uncertain significance not provided 2019-08-01 criteria provided, single submitter clinical testing
Invitae RCV001055929 SCV001220344 uncertain significance Hypertrophic cardiomyopathy 2019-12-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu165*) in the TNNI3 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 24793961). ClinVar contains an entry for this variant (Variation ID: 383149). The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TNNI3 cause disease. 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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