ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.2602G>A (p.Ala868Thr) (rs143150260)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766981 SCV000619757 uncertain significance not provided 2018-08-02 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ACTN2 gene. The A868T variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 12/270,052 alleles from individuals of various ethnic backgrounds in large population cohorts (Lek et al., 2016). The A868T 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. Nevertheless, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000803810 SCV000943696 uncertain significance Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 868 of the ACTN2 protein (p.Ala868Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs143150260, ExAC 0.03%). This variant has not been reported in the literature in individuals with ACTN2-related disease. ClinVar contains an entry for this variant (Variation ID: 228435). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000217264 SCV000271496 uncertain significance not specified 2015-05-28 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Ala868Thr var iant in ACTN2 has not been previously reported in individuals with cardiomyopath y, but has been identified in 3/10380 African chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs143150260). Alanine (Ala) at position 868 is not conserved in mammals or evolutionarily distant spe cies and the change to threonine (Thr) is present in 2 mammals (bushbaby and ten rec) and in frog, suggesting this change may be tolerated. In summary, while the clinical significance of the p.Ala868Thr variant is uncertain, the presence of the variant amino acid in other mammals suggests this variant is more likely to be benign.

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