ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.697G>A (p.Glu233Lys) (rs730881107)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159309 SCV000209255 uncertain significance not provided 2017-04-24 criteria provided, single submitter clinical testing p.Glu226Lys (GAA>AAA): c.676 G>A in exon 13 of the TNNT2 gene (NM_001001430.1). The Glu226Lys variant in the TNNT2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Glu226Lys results in a non-conservative amino acid substitution of a negatively charged Glutamic acid with a positively charged Lysine at a position that is conserved across species. The Glu226Lys variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Hereditary dilated cardiomyopathy (DCM) is primarily an autosomal dominant disease characterized by left ventricular enlargement and systolic dysfunction in the absence of other cardiac, systemic or environmental causes (Hershberger R et al., 2009). Left ventricular noncompaction (LVNC) is a rare cardiomyopathy characterized by deep trabeculations with intertrabecular recesses in the ventricular wall (Callis T et al., 2010). LVNC and DCM can lead to progressive deterioration of cardiac function, arrhythmias, and sudden cardiac death, although some individuals may be asymptomatic. Hereditary DCM is most frequently caused by mutations in genes encoding for sarcomeric proteins in the cardiac muscle, or in the gene encoding the nuclear envelope protein lamin A/C (LMNA). Less commonly, DCM and LVNC can be caused by mutations in genes associated with metabolic or mitochondrial disorders (Callis T et al., 2010; Hershberger R et al., 2009). The variant is found in DCM,CARDIOMYOPATHY panel(s).
Invitae RCV000540890 SCV000646907 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2017-03-02 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 226 of the TNNT2 protein (p.Glu226Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TNNT2-related disease. ClinVar contains an entry for this variant (Variation ID: 181626). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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