Submission Details

ANK1 was first reported in relation to autosomal recessive Hereditary Spherocytosis (HS) in 1996 (Eber, PMID: 8640229). HS is characterized by the presence of spherical-shaped erythrocytes, termed spherocytes, on a peripheral blood smear. Spherocytes can accumulate in the spleen, causing anemia, jaundice, and splenomegaly. Complications include hyperbilirubinemia in neonates, cholelithiasis, hemolytic episodes, aplastic crises, and iron overload, although mild cases may go undetected without a blood smear. Spherocytosis, Type 1 (OMIM:182900) is associated with ANK1 with both autosomal dominant and autosomal recessive forms of HS having been reported. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we have split these two inheritance patterns for gene-disease validity curation. The dominant form of Spherocytosis, Type 1 (OMIM:182900) was curated separately and reached Definitive and the mechanism of pathogenicity is known to be loss of function of ANK, leading to a loss of flexibility and shape of the erythrocyte membrane. For the recessive form, for 3/7 families, only one allele or two in cis alleles was reported. At least 7 variants (missense, deep intronic, and promoter variants) have been reported in humans (PMIDs: 8640229, 11102985, 17327413, 16037067). However, 4 of these variants (including the commonly reported c.127-39509T>C (c.-108T-C) variant) are too frequent in gnomAD to cause disease (ranging from 0.2% to 11% allele frequency). These frequent variants were present in 5/7 families. In the families with recessive inheritance claimed, most heterozygous parents, when available for phenotyping, were actually mildly affected with features of HS, contradicting a pure recessive form of inheritance. In summary, evidence supporting this gene-disease relationship includes minimal case-level data (2/7 families are scored) and the only functional evidence includes gene expression consistent with the location of disease (PMID: 2139228).In conclusion, while the experts felt that there could exist hypomorphic alleles that have mild enough effect to lead to disease only when found on both alleles, the experts felt that there was insufficient evidence for a pure recessive form of this gene-disease relationship with existing cases more likely explained by a dosage effect of pathogenic variants. A Limited classification was approved by the ClinGen General Gene Curation Expert Panel on the meeting date June 23, 2021 (SOP Version 8).