ClinVar Miner

Submissions for variant NM_005159.5(ACTC1):c.755T>C (p.Ile252Thr) (rs730880398)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157788 SCV000207718 uncertain significance not provided 2017-09-01 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ACTC1 gene. The I252T variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The I252T 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. In addition, this substitution occurs at a position that is conserved across species. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, the I252T variant lacks sufficient evidence, including observation in a significant number of affected individuals, complete segregation studies, and functional characterization, that would further clarify its potential pathogenicity.
Invitae RCV000814581 SCV000954994 uncertain significance Familial hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 252 of the ACTC1 protein (p.Ile252Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with dilated cardiomyopathy (PMID: 28416588). ClinVar contains an entry for this variant (Variation ID: 180763). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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