ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.625G>A (p.Glu209Lys) (rs727504268)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154256 SCV000203911 uncertain significance not specified 2013-02-13 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000766927 SCV000209198 uncertain significance not provided 2016-03-02 criteria provided, single submitter clinical testing While the E209K variant has not been published as a pathogenic variant or a benign variant to our knowledge, it has been identified in other individuals tested for cardiomyopathy at GeneDx. In addition, it has been reported as a variant of uncertain significance in multiple individuals from a single family tested at an external laboratory (Landrum et al., 2014). A different missense change at the same residue (E209A) has been reported as a possibly deleterious mutation in four individuals with hypertrophic or restrictive cardiomyopathy (van den Wijngaard A et al., 2011). The E209K variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E209K 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. This substitution occurs at a position that is conserved in mammals and in silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, missense variants in nearby residues (G203S, G203R, R204C, R204H, K206Q, K207T) have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001049450 SCV001213499 uncertain significance Hypertrophic cardiomyopathy 2019-07-31 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 209 of the TNNI3 protein (p.Glu209Lys). 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 been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 177666). 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.

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