Submission Details

Pending. ANG was first reported in relation to autosomal dominant amyotrophic lateral sclerosis in 2004 (Greenway et al., PMID 15557516). At least 31 unique missense variants have been reported in humans, of these 16 were eligible for scoring using a minor allele frequency threshold of <0.000005 in the gnomAD v2.1.1 non-neurological conditions dataset. Evidence supporting this gene-disease relationship consists mostly of individual case reports with evidence of angiogenin expression in spinal motor neurons making up the experimental data. Summary of Case Level Data: 2.7 POINTS Variants in this gene have been reported in at least 70 probands in 21 publications (PMIDs 15557516, 16501576, 17886298, 17703939, 18087731, 18852347, 19153377, 19363631, 20577002, 21621297, 22190368, 22292798, 22292843, 22645277, 22752089, 23155438, 23228179, 28160950, 28444446, 31025543, 31432357) of which 23 probands from 6 studies (PMIDs 15557516, 16501576, 17886298, 18087731, 22190368, 22292843) contribute to the case level data score due to many of the most highly reported variants also being present at high frequencies in control datasets and gnomAD v2.1.1 non-neuro. Common functional assays demonstrating the effect of variants on the gene product included nuclear translocation, ribonuclease activity, angiogenic activity and morphology of cultured motor neurons co-cultured with angiogenin with ALS associated variants (PMIDs 17916583, 17886298, 23047679, 22292843, 31025543, 31432357). These assays were not used to increase case-level evidence as functional changes were observed in benign variants for example K41I [K17I]. Evidence of disruption to stress granule formation of variant K64I [K40I] was the only eligible functional data to increase the score of a case-level variant report (PMID 23047679).
Summary of Experimental Data: 0.5 POINTS Angiogenin is expressed in fetal and adult spinal motor neurons and endothelial cells (PMID 17886298). A phenotype rescue study was performed on SOD1 G93D mice. In this experiment it was shown that delivery of recombinant angiogenin ameliorated motor symptoms and extended lifespan. However, the phenotype was not fully rescued, and it was not clear what cellular process caused the underlying the results, so this evidence did not contribute towards the overall score (PMID 19109488). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.