CALR3 was first associated with hypertrophic cardiomyopathy (HCM) in 2007 (Chiu et al, PMID 17655857). However, these 2 unique variants from the 2 probands in this publication now show no evidence to support the association of CALR3 with HCM. This is due to one variant reported in a proband with 2 missense variants in MYBPC3, and the other variant being seen frequently in control populations. Both variants have no experimental evidence to support their pathogenicity. There is no additional case evidence. The mechanism for disease is unknown. There is no experimental evidence to support the gene-disease association. There is new contradictory evidence. One publication showed CALR3 did not segregate with disease in some families, a large proportion of probands with CALR3 variants had at least 1 VUS in another cardiomyopathy gene, no significant difference in a case-control study, and that CLAR3 protein was not expressed in human myocardial tissue (Verhagen et al, 2018, PMID 29988065). Two previous publications also shown no cardiac expression and no cardiac abnormalities in CALR3 knockout animal models (Ikawa et al, 2011, PMID 21131354; Hung et al, 2013, PMID 23873374). In summary, the evidence to support the gene-disease association between CALR3 and HCM is disputed. This is due to a lack of supportive evidence since the previous curation and new convincing evidence has emerged that contradicts the gene-disease association. This gene-disease association was originally evaluated by the ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel on February 7, 2017. It was reevaluated on January 11th, 2023. As a result of this reevaluation, the classification changed from limited to disputed.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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