The CSRP3 gene has been associated with semidominant hypertrophic cardiomyopathy in 73 probands across 17 publications. Semidominance includes both dominant and recessive inheritance patterns where individuals with heterozygous variants have an intermediate phenotype and individuals with homozygous variants have a more severe phenotype and/or earlier onset. Twenty-five unique variants (16 missense, 4 frameshift, 2 nonsense, 2 canonical splice site, and 1 indel) that have been reported in humans (PMIDs: 16352453, 18505755, 15781201, 23396983, 26656175, 21425739, 12642359, 19035361, 25351510, 23861362, 20087448, 30012424, 34558151, 33035702, 31919335, 33012304, 37431535) are included in this curation. CSRP3 was first associated with this disease in humans in 2003 (Geier et al., PMID 12642359). This gene-disease relationship has been studied in at least 5 case-control studies (PMIDs: 23396983, 28082330, 27532257, 37431535) at the aggregate variant level and showed nominally significant case excess. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is loss of function.
The gene-disease relationship is also supported by expression studies (Uhlén M, et al., 2015, PMID: 25613900), protein interaction with alpha-actinin (Knöll R, et al., 2002, PMID: 12507422), biochemical function (Hoffmann C, et al., 2014, PMID: 24934443), mouse models (Ehsan M, et al., 2018, PMID: 30048712, Arber S, et al., 1997, PMID: 9039266), a cell culture model (Li X, et al., 2019, PMID: 31406109), and a rescue model (Arber S, et al., 1997, PMID: 9039266). In summary, there is definitive evidence supporting the relationship between CSRP3 and semidominant hypertrophic cardiomyopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This gene-disease pair was originally evaluated by the Hypertrophic Cardiomyopathy GCEP on December 19, 2017. It was re-evaluated on August 9, 2023 by the ClinGen Hereditary Cardiovascular Disease GCEP (SOP Version 9). As a result of this reevaluation, the classification increased from Moderate to Definitive with the addition of a new case-level and experimental data and the inclusion of recessive data given the change to a semidominant mode of inheritance.
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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