LIMS2, also known as PINCH2, was first reported in relation to autosomal recessive limb-girdle muscular dystrophy in 2015 (Chardon JW et al., PMID:25589244). Three missense variants have been reported in a pair of siblings with the limb-girdle phenotype in the literature; this is the only report known to have been published of a LIMS2 variant identified in a patient with autosomal recessive limb-girdle muscular dystrophy. None of these variants have functional evidence in support of pathogenicity and the mechanism for disease is unknown.
ClinVar contains submissions for variants within this gene; the panel contacted submitters of pathogenic and likely pathogenic ClinVar contributions and found no additional evidence to support this gene-disease relationship.
The loxP/Cre system was used to knock out LIMS2 in a mouse model. The resulting LIMS2 deficient mice showed no apparent phenotype when compared to their wild-type and heterozygous littermates (PMID:16317048). RNA sequencing of total RNA from 20 human tissues shows non-specific expression of LIMS2 in skeletal muscle, low to moderate in comparison to expression in other tissues (NCBI Bioproject:PRJNA280600).
The evidence of this gene-disease relationship is limited to a few cases carrying missense variants and presenting with genetically heterogeneous phenotypes with a sum of genetic evidence below 0. No compelling experimental evidence is available.
In summary, the evidence supporting the relationship between LIMS2 and autosomal recessive limb-girdle muscular dystrophy has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role LIMS2 plays in this disease.
This classification was approved by the ClinGen Muscular Dystrophies and Myopathies Gene Curation Expert Panel on the meeting date November 12, 2024 (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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