ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.626A>C (p.Glu209Ala) (rs730881083)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000505779 SCV000209199 uncertain significance not provided 2017-03-07 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TNNI3 gene. The E209A variant has been reported as a possibly deleterious variant in at least 5 unrelated probands with cardiomyopathy (van den Wijngaard et al., 2011); however, familial segregation information and in vitro functional studies were not included. Nevertheless, the E209A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved in mammals. Finally, in silico analysis predicts this variant is probably damaging to the protein structure/function.
Invitae RCV000809873 SCV000950054 uncertain significance Hypertrophic cardiomyopathy 2018-11-01 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 209 of the TNNI3 protein (p.Glu209Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with hypertrophic cardiomyopathy and in one individual with a combination of hypertrophic and restrictive cardiomyopathy (PMID: 21533915, 27532257). ClinVar contains an entry for this variant (Variation ID: 181595). 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000505779 SCV001743879 pathogenic not provided no assertion criteria provided clinical testing

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