ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.293G>A (p.Arg98Gln) (rs747522089)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523164 SCV000617287 uncertain significance not provided 2017-08-01 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TNNI3 gene. The R98Q variant has been published in association with HCM (Rani et al., 2012). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R98Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position where amino acids with similar properties to arginine (R) are tolerated across species. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Color Health, Inc RCV000772060 SCV000905088 uncertain significance Cardiomyopathy 2018-10-15 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the TNNT-binding region of the TNNI3 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an Indian individual affected with severe hypertrophic obstructive cardiomyopathy with a history of sudden cardiac death in three members of the family (PMID: 22876777). This variant has also been identified in 6/277114 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.

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