ClinVar Miner

Submissions for variant NM_005159.5(ACTC1):c.529A>G (p.Ile177Val) (rs730880392)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000576276 SCV000676969 uncertain significance Familial hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 2019-10-25 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 177 of the ACTC1 protein (p.Ile177Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ACTC1-related disease. ClinVar contains an entry for this variant (Variation ID: 180757). 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 C25"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770515 SCV000901960 uncertain significance Cardiomyopathy 2017-01-26 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223764 SCV000280038 uncertain significance not specified 2014-07-05 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. ACTC1 p.Ile177Val We consider this variant a variant of uncertain significance. The variant is novel. In silico analysis with PolyPhen-2 predicts the variant to be benign (HumVar score is 0.050). The isoleucine at codon 177 is completely conserved across species, as are neighboring amino acids. Other variants have been observed in association with disease at nearby codons (p.Ala172Thr (we classify as variant of uncertain significance), p.Tyr168Cys, p.Pro166Ala). This is a conservative amino acid substitution (Grantham score is 29). In total the variant has not been seen in ~6500 individuals from publicly available population datasets. There is no variation at codon 177 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 3rd, 2014). Of note, there are only three nonsynomous variants (all missense) in this gene in the ESP data set. 5 of 6500 individuals (0.077%) in this dataset have a nonsynomous variant in ACTC1. There is also no variation at this codon listed in dbSNP (as of July 5th, 2014).

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