ClinVar Miner

Submissions for variant NM_005159.5(ACTC1):c.664G>A (p.Ala222Thr)

dbSNP: rs1555418793
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV000513489 SCV000608714 uncertain significance not provided 2017-05-01 criteria provided, single submitter clinical testing
GeneDx RCV000513489 SCV002552689 uncertain significance not provided 2022-07-14 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust RCV003325959 SCV003853402 likely pathogenic Dilated cardiomyopathy 1R 2023-03-23 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003392343 SCV004121006 likely pathogenic ACTC1-related condition 2023-02-03 criteria provided, single submitter clinical testing The ACTC1 c.664G>A variant is predicted to result in the amino acid substitution p.Ala222Thr. To our knowledge, this variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been reported to have occurred de novo in an individual with dilated cardiomyopathy; however, this study was not yet peer-reviewed and the data should be interpreted with caution (Table 3.1, https://ora.ox.ac.uk/objects/uuid:5961cb6e-f6b6-48b3-8f76-aa31b5c31c12/files/dsx61dm71v). This variant has also been documented to have occurred de novo in an individual with ACTC1-associated phenotypes at PreventionGenetics (internal data). This variant is interpreted as likely pathogenic.
Invitae RCV003766893 SCV004605465 uncertain significance Hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 2023-07-21 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 222 of the ACTC1 protein (p.Ala222Thr). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ACTC1 protein function. ClinVar contains an entry for this variant (Variation ID: 444338). This variant has not been reported in the literature in individuals affected with ACTC1-related conditions. This variant is not present in population databases (gnomAD no frequency).

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