BLVRA

Inheritance Pattern: AD

Disease ID:MONDO:0013595

Submitter: Orphanet

Inheritance Pattern: Unknown

Disease ID:MONDO:0013595

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0013595

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0013595

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0013595

Submitter: ClinGen

*BLVRA* enocdes Biliverdin reductase A (BVR-A) and was first reported in relation to hyperbiliverdemia by Gafvels et al. (2009). Abnormality of heme degradation pathway, especially of the enzyme biliverdin reductase responsible for the conversion of biliverdin to bilirubin, leads to the appearance of hyperbiliverdinemia. The accumulation of biliverdin in the plasma appears with greenish coloration of the skin, urine, or tissues. Apart from enzyme defects, hyperbiliverdinemia may also be caused by liver dysfunction or decompensated liver cirrhosis, through hepatocellular damage, thereby impairing the processing and excretion of bilirubin into the blood and contributing to elevated biliverdin levels. Homozygous mutations in the BLVRA gene cause this disease. **Summary of Case Level Data (4.5 points):** 2 probands were scored with 1 nonsense variant (PMID: 21278388). **Summary of Experimental Evidence (4.5 points):** Human biliverdin IXalpha reductase (BVR) was cloned, sequenced, and characterized, revealing its dual pH and cofactor dependence, Zn metalloprotein nature, and similarity to rat BVR, with distinct differences in cofactor use and charge variants (PMID: 8631357). Bilirubin, a heme catabolism by-product antioxidant, reduced oxidative stress in vivo, as indicated by markers of oxidative stress were increased in Bvra–/– mice with low bilirubin levels. The study generated and characterized Bvra–/– mice, lacking biliverdin reductase-a, which caused plasma biliverdin to be elevated while plasma bilirubin was nearly undetectable and bile was green, mimicking "green jaundice". Such mice exhibited higher oxidative stress, marked by increased plasma CE-OOH and oxidized erythrocyte Prx2, indicating the physiological antioxidant role of bilirubin (PMID: 29195835). The accumulation of bile acids in cholestasis, leading to oxidative stress, was further linked to BVRα deficiency, which causes green jaundice; however, biliverdin (BV) still provides antioxidant protection independent of BVRα, without significantly affecting oxidative stress or cell death in the presence of deoxycholic acid (PMID: 27387768). In summary, experimental and clinical evidence supports a moderate gene- disease relationship between *BLVRA* and autosomal recessive Hyperbiliverdinemia. While more evidence is required to meet a definitive classification, no contradictory evidence has been identified. This classification was approved by the ClinGen IEM GCEP on January 10, 2025 (SOP Version 11).