ClinVar Miner

Submissions for variant NM_005159.5(ACTC1):c.563C>T (p.Thr188Ile) (rs730880394)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157784 SCV000207714 uncertain significance not provided 2015-09-28 criteria provided, single submitter clinical testing p.Thr188Ile (ACT>ATT): c.563 C>T in exon 4 of the ACTC1 gene (NM_005159.4). The Thr188Ile variant in the ACTC1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Thr188Ile results in a non-conservative amino acid substitution of a polar Threonine with a non-polar Isoleucine at a position that is conserved across species. In silico analysis predicts Thr188Ile is damaging to the protein structure/function. The Thr188Ile 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. Nevertheless, no mutations in nearby codons have been reported in association with cardiomyopathy.With the clinical and molecular information available at this time, we cannot definitively determine if Thr188Ile is a disease-causing mutation or a rare benign variant. The variant is found in DCM panel(s).
Invitae RCV000696769 SCV000825346 uncertain significance Familial hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 2019-06-24 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 188 of the ACTC1 protein (p.Thr188Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ACTC1-related disease. ClinVar contains an entry for this variant (Variation ID: 180759). 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: "Benign"; Align-GVGD: "Class C65"). 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000157784 SCV000924714 uncertain significance not provided 2016-04-14 no assertion criteria provided provider interpretation

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