ANK1

Inheritance Pattern: SD

Disease ID:MONDO:0008447

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0008447

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0008447

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0008447

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0008447

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Inheritance Pattern: AD

Disease ID:MONDO:0019350

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0019350

Submitter: ClinGen

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).

Inheritance Pattern: AD

Disease ID:MONDO:0019350

Submitter: ClinGen

ANK1 was first reported in relation to autosomal dominant Hereditary Spherocytosis (HS) in 1989 (Davies and Lux, PMID: 2675425). 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. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in inheritance pattern between autosomal dominant and autosomal recessive HS. Therefore, the following disease entities have been split by inheritance pattern into multiple disease entities with Spherocytosis, Type 1 (OMIM:182900) being the dominant form and the split curation for autosomal recessive HS will be curated separately. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Nine variants (missense, nonsense, frameshift, splicing) that have been reported in nine probands in three publications (PMIDs: 8640229, 31016877, 32436265) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) was reached. 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. This gene-disease association is also supported by multiple animal models, expression studies, in vitro functional assays, and biochemical function experiments (PMIDs: 2137557, 2139228, 1826225, 24688720, 31147440, 31016877). More evidence is available in the literature, but the maximum score for experimental evidence (6 pts.) was reached. In summary, ANK1 is definitively associated with autosomal dominant Hereditary Spherocytosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen General Gene Curation Expert Panel on the meeting date March 24, 2021 (SOP Version 8).