ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.581A>C (p.Asn194Thr) (rs730881081)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620710 SCV000737302 uncertain significance Cardiovascular phenotype 2017-08-08 criteria provided, single submitter clinical testing The p.N194T variant (also known as c.581A>C), located in coding exon 8 of the TNNI3 gene, results from an A to C substitution at nucleotide position 581. The asparagine at codon 194 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) testing cohort; however, clinical details were not provided (Walsh R et al. Genet. Med., 2017 Feb;19:192-203). An alternate substitution at this amino acid position, p.N194S, has been detected in at least two patients with confirmed HCM (Coppini R et al. J. Am. Coll. Cardiol., 2014 Dec;64:2589-600; Cecconi M et al. Int. J. Mol. Med., 2016 Oct;38:1111-24). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000803326 SCV000943190 uncertain significance Hypertrophic cardiomyopathy 2018-10-16 criteria provided, single submitter clinical testing This sequence change replaces asparagine with threonine at codon 194 of the TNNI3 protein (p.Asn194Thr). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and threonine. This variant is present in population databases (rs730881081, ExAC 0.001%). This variant has been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 519178). 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: "Probably Damaging"; 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.
Color Health, Inc RCV001187551 SCV001354371 uncertain significance Cardiomyopathy 2021-01-05 criteria provided, single submitter clinical testing This missense variant replaces asparagine with threonine at codon 194 of the TNNI3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has been identified in 1/249570 chromosomes 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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