ALPK3 was first reported in relation to autosomal recessive hypertrophic cardiomyopathy in 2016 (Almomani et al., 2016; PMID:26846950). At least 22 variants (nonsense, frameshift, missense, and splice site) that have been reported in 19 probands in 8 publications (PMIDs: 26846950, 27106955, 33076350, 28630369, 30046096, 31074094, 34862804, 32480058) are included in this curation. Variants in this gene segregated in at least 4 families. More evidence is available in the literature, however the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of disease is homozygous loss of function. This gene-disease relationship is supported by biochemical function, expression, functional alterations (in patient and non-patient cells), and an animal model (PMIDs: 27106955, 11418590, 21441111). In summary, ALPK3 is DEFINITIVELY associated with autosomal recessive hypertrophic cardiomyopathy, and has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. An analysis to determine the strength of evidence for ALPK3 in an autosomal dominant cardiomyopathy will be performed separately.
The relationship between ALPK3 and autosomal recessive hypertrophic cardiomyopathy was originally evaluated by the ClinGen Hypertrophic Cardiomyopathy GCEP on February 2, 2017. It was re-evaluated on February 7, 2022. As a result of this recuration, the classification changed from the original Strong to Definitive. This classification was approved by the ClinGen Hereditary Cardiovascular Diseases GCEP on February 7, 2022.
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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