ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.184G>A (p.Glu62Lys) (rs1357844466)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000530156 SCV000623776 uncertain significance Hypertrophic cardiomyopathy 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 62 of the TNNI3 protein (p.Glu62Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a TNNI3-related disease. An algorithm developed specifically for the TNNI3 gene (PMID: 21310275), suggests that this missense change is likely to be deleterious. However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. In summary, this variant has uncertain impact on TNNI3 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786225 SCV000924963 uncertain significance not provided 2017-12-04 no assertion criteria provided provider interpretation We identified in this variant in a patient with personal and family history of DCM. Testing was performed at Invitae. SCICD Classification: variant of uncertain significance based on absence in the general population and lack of case data. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: TNNI3 encodes the cardiac muscle isoform of troponin I. It has been associated with hypertrophic, dilated, and restrictive cardiomyopathy. Case data (not including our patient): 0 · ClinVar: not present · Cases in the literature: none reported Segregation data: none reported Functional data: none reported In silico data (missense variants only): Per the test report, "An algorithm developed specifically for the TNNI3 gene (PMID: 21310275), suggests that this missense change is likely to be deleterious. The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine." Nearby pathogenic variants at this codon or neighboring codons: None Population data: Absent The variant is not present in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Per Varsome.org, the average coverage at that site in genomes is 32x whereas in exomes it is 67x.

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