ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.2423C>T (p.Thr808Ile) (rs148833906)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000459293 SCV000553764 uncertain significance Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2019-10-17 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 808 of the ACTN2 protein (p.Thr808Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs148833906, ExAC 0.08%). This variant has not been reported in the literature in individuals with ACTN2-related disease. ClinVar contains an entry for this variant (Variation ID: 412276). 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: "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.
GeneDx RCV000523122 SCV000621256 uncertain significance not provided 2017-10-02 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ACTN2 gene. The T808I variant has not been published as pathogenic or been reported as benign to our knowledge. This variant has been observed in 10/24032 (0.04%) alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016). The T808I 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. However, while this substitution occurs at a position that is conserved in mammals, isoleucine (I) is the wild-type residue at this position in at least one non-mammalian species. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678698 SCV000804860 uncertain significance Dilated cardiomyopathy 2016-11-30 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.