KLHL41 was first reported in relation to autosomal-recessive nemaline myopathy 9 in 2013 (Gupta VA, et al., PMID: 24268659). At least 8 unique variants (e.g. missense, in-frame indel, frameshift, large deletion) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Summary of Case Level Data: 3.5 POINTS. Variants in this gene have been curated from 5 probands in 3 publications ( PMID: 24268659, 28939701, 28749478). The mechanism for the disease is homozygous loss of function (PMID: 24268659). This gene-disease association is supported by a mouse model (PMID: 28826497) which recapitulates disease as well as a zebrafish myopathy model which was rescued by expression of human KLHL41 (PMID: 24268659). Additionally, the function of KLHL41 in regulation of the thin filaments (PMIDs: 28826497, 30986853) its expression in skeletal muscle (PMID: 28826497), and its interaction with components of the sarcomere (PMID: 28826497), all provide further evidence. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.
This gene-disease pair was originally evaluated by the CM GCEP on 11/5/2019. It was reevaluated on 10/21/2024. As a result of this reevaluation no new evidence was identified and the classification remained at Moderate (SOP Version 11).
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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