ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.114A>T (p.Lys38Asn) (rs730881066)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159209 SCV000209155 likely pathogenic not provided 2012-09-12 criteria provided, single submitter clinical testing The Lys38Asn variant in the TNNI3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Lys38Asn results in a non-conservative amino acid substitution of positively charged Lysine with a neutral, polar Asparagine at a position that is conserved across species. A mutation in a nearby residue (Lys36Gln) has been reported in association with DCM, supporting the functional importance of this region of the protein. In addition, Carballo et al. note Lys36 is the first of three Lysine residues, including Lys38, and the loss of a positive charge resulted in reduced interaction with the calcium binding site of troponin C. Furthermore, the NHLBI ESP Exome Variant Server reports Lys38Asn was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations.In summary, the Lys38Asn variant in the TNNI3 gene is likely a mutation, however the possibility it is a rare benign variant cannot be excluded. The variant is found in DCM panel(s).
Color Health, Inc RCV001525777 SCV001735965 uncertain significance Cardiomyopathy 2020-07-28 criteria provided, single submitter clinical testing This missense variant replaces lysine with asparagine at codon 38 of the TNNI3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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