SEC61A1

Inheritance Pattern: AD

Disease ID:MONDO:0014891

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0014891

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0014891

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0100337

Submitter: ClinGen

The relationship between SEC61A1 and SEC61A1 deficiency, an autosomal dominant disorder, was evaluated using the ClinGen Clinical Validity Framework as of June, 2021. SEC61A1 encodes the alpha subunit of the heteromeric SEC61 complex, which also contains beta and gamma subunits. It has a role in the insertion of secretory and membrane polypeptides into the endoplasmic reticulum. SEC61A1 deficiency is characterized by hypogammaglobulinemia and recurrent respiratory infections (Tangye et al; PMID: 31953710). Patients in the literature have been described with different diagnosed entities such as Autosomal dominant tubulointerstital kidney disease, Primary antibody deficiency and severe congenital neutropenia. SEC61A1 was first reported in relation to autosomal dominant SEC61A1 deficiency in 2016 (Bolar et al, PMID: 27392076). Variants reported in this gene thus far include missense and nonsense variants. Evidence supporting this gene-disease relationship includes case-level data, including segregation data, and experimental data. Summary of Case Level Data (8.5 points): There have been 6 patients from 4 publications, till date, reported with heterozygous variants in SEC61A1 (PMID: 27392076, 28782633, 32325141, 33185949). The mechanism of disease is reported to be haploinsufficiency or a dominant negative effect leading to functional haploinsufficiency. Summary of experimental data (2 points): This gene-disease association is supported by in-vitro functional assays and an animal model. SEC61A1 is localized subcellularly within the endoplasmic reticulum, but mutant SEC61A1 protein is found in clumps and localized in the ER and Golgi (PMID: 27392076). ER stress and increased calcium leak are reported as disease pathomechanism and are demonstrated in patients as well as experimental systems (PMID: 32325141). Knock-down of SEC61A1 using CRISPR/Cas9 or splice morpholino techniques in zebrafish results in pronephric tubular atrophy (PMID: 27392076) and partially recapitulates the human phenotype. In summary, the level of evidence to support the gene-disease relationship of SEC61A1 and autosomal dominant SEC61A1 deficiency is moderate. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. OMIM entities: Tubulointerstitial kidney disease, autosomal dominant, 5 (MIM: 617056). Additional entities from the literature: familial juvenile hyperurecemic nephropathy (PMID: 31488840), Primary antibody deficiency (PMID: 28782633) and severe congenital neutropenia (PMID: 32325141). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, while multiple disease assertions are made in the literature with the same autosomal dominant inheritance, there is limited evidence relating to the molecular mechanism(s) AND phenotypic variability in the above mentioned disease entities. PMID: 31953710 suggests the term SEC61A1 deficiency that encompasses all the phenotypes. Therefore, all of the disease entities have been lumped into one disease entity, autosomal dominant SEC61A1 deficiency. This classification was approved by the ClinGen Antibody Deficiencies Gene Curation Expert Panel on the meeting date June 15, 2021 (SOP Version 8).

Inheritance Pattern: AD

Disease ID:MONDO:0958013

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0014891

Submitter: G2P