Submission Details

hnRNPA1 encodes heterogeneous nuclear ribonucleoprotein A1, which is involved in packaging of pre-mRNA into hnRNP particles, transport of poly(A) mRNA from the nucleus to the cytoplasm and modulation of splice site selection. hnRNPA1 was first reported in relation to multisystem proteinopathy (inclusion body myopathy; OMIM: 615424) and familial amyotrophic lateral sclerosis 20 (ALS 20; OMIM: 615426) in linkage analyses of multiple families, each with differing phenotypes, in 2013 (Kim et al., PMID: 23455423). The gene was later associated with distal hereditary motor neuropathy (MONDO:0018894) and distal myopathy (OMIM: 610099) in a candidate gene analysis of multiple families, each with differing phenotypes, in 2021 (Beijer et al., PMID: 34291734). Following assessment of the criteria outlined by the ClinGen Lumping and Splitting Working Group, the ALS GCEP found that although there were not clear differences in molecular mechanisms and inheritance patterns between hnRNPA1’s associations with inclusion body myopathy, distal hereditary motor neuropathy, or distal myopathy and with ALS 20, there was observable phenotypic variability. Additionally, there was concern that lumping the phenotypes would falsely inflate the score of hnRNPA1 based on the wide range of associations. Therefore, the phenotypes were split from ALS 20.

No case-control analyses were reported for the curation of hnRNPA1; however, one family presenting with flail arm syndrome ALS was scorable with four segregations and a calculated LOD score of 1.2 (Liu et al., 2016, PMID: 27694260). Additionally, seven variants reported in seven probands across six publications (PMID: 23455423, 27694260, 29033165, 32616036, 34291734, 36314424) were scored in this curation. Importantly, four of the variants had functional evidence supporting their pathogenicity. Based on the curation, a genetic evidence score of 2.3 was reached. The gene-disease curation was also supported by experimental evidence, including functional evidence of expression and protein interactions with other relevant ALS-associated proteins from five publications (PMID: 33087501, 28077597, 27460707, 25616961, 25338872). Notably, the ALS GCEP chose to apply a gene-specific attenuation to downgrade certain protein interaction scores due to the high number of protein interactions observed for hnRNPA1 with ALS-associated proteins. Only interactions that were proven to be disrupted by variants in either hnRNPA1 or the gene encoding the interacting protein were given full scores of 0.5. An experimental evidence score of 2.0 was reached

In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to establish hnRNPA1’s relationship with ALS 20, particularly regarding whether there is case-control evidence to suggest an association and the molecular mechanism of pathogenic variants, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen ALS GCEP on May 14, 2024 (SOP Version 10).