Pathonign variants in recessive disorders: How extremely hypomorphic variants can be pathogenic and benign depending on the allele in trans - PubMed
4 hours ago
- #variant pathogenicity
- #recessive disorder
- #hypomorphic allele
- Some hypomorphic variants in recessive disorders can be pathogenic when paired with a loss-of-function variant (yielding <50% protein activity) but benign when homozygous (yielding >50% protein activity).
- Such variants, termed 'pathonign', are weakly eliminated by natural selection, leading to higher population frequencies that can misleadingly categorize them as benign per typical criteria.
- An example is the ABCA4 variant c.5603A>T (p.Asn1868Ile) in Stargardt disease-1, pathogenic in trans with null or missense variants but not when homozygous.