ClinVar Miner

Submissions for variant NM_005159.5(ACTC1):c.83C>T (p.Ala28Val) (rs397517072)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000043642 SCV000062012 uncertain significance not specified 2012-11-23 criteria provided, single submitter clinical testing The Ala28Val variant in ACTC has not been reported in the literature nor detecte d in large and broad populations (European and African American) sequenced by th e NHLBI Exome Sequencing Project (, but has be en previously identified in one individual with HCM by our laboratory (unpublish ed data). Computational analyses (biochemical amino acid properties, conservatio n, AlignGVGD, PolyPhen2, and SIFT) suggest that the Ala28Val variant may impact the protein, though this information is not predictive enough to determine patho genicity. Additional information is needed to fully assess the clinical signific ance of the Ala28Val variant.
GeneDx RCV000766335 SCV000321377 uncertain significance not provided 2018-05-17 criteria provided, single submitter clinical testing The A28V variant in the ACTC1 gene has been reported previously as a variant of uncertain significance in a single individual with hypertrophic cardiomyopathy (Alfares et al., 2015); it is unknown if this individual harbored any variants in other genes associated with cardiomyopathy. The A28V 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. The A28V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In addition, a missense variant in a nearby residue (F23L) has been reported in the Human Gene Mutation Database in association with hypertrophic cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret A28V as a variant of uncertain significance.
Invitae RCV000823415 SCV000964275 uncertain significance Familial hypertrophic cardiomyopathy 11; Dilated cardiomyopathy 1R; Atrial septal defect 5 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 28 of the ACTC1 protein (p.Ala28Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 50937). 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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