Submission Details

ANKRD1 was first reported in relation to hypertrophic cardiomyopathy (HCM) in humans in 2009, where 2 unique missense variants were reported in probands with no family history of cardiomyopathy (Arimura T, et al., 2009, PMID: 19608031). ANKRD1 has been associated with autosomal dominant HCM in 2 probands from 1 publication. Additional missense variants have been reported in humans, but either the frequency of the variants were too high, there were homozygotes present in gnomAD, the phenotypes more closely resembled DCM, or the probands had a variant in another HCM gene (Arimura T, et al., 2009, PMID: 1960803; Ng D, et al., 2013, PMID: 23861362; Cecconi M, et al., 2016, PMID: 27600940). This gene-disease relationship is supported by expression data, a cell culture model, and an animal model. High tissue specificity in the heart has been observed for this gene (Uhlén M, et al., 2015, PMID: 25613900). Expression studies in mature rat cardiomyocytes and the examination of contraction parameters using engineered heart tissues support the gene-disease association (Crocini C, et al., 2013, PMID: 23572067). Overexpression of ANKRD1 in mice with transverse aortic constriction was shown to exacerbate pathological cardiac remodeling through activation of the calcineurin/nuclear factor of activated T-cells pathway, a signaling pathway known to have an important role in cardiac hypertrophy (Chen C, et al., 2014, PMID: 25089522). This classification was originally approved by the ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel on September 19th, 2017, with a classification of limited. It was reevaluated by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel on February 8th, 2023. As a result of this reevaluation, the classification was changed from limited to disputed.