ATP6V1A was first reported in relation to ATP6V1A-CDG (also known as (also known as autosomal recessive cutis laxa 2D), an autosomal recessive congenital disorder of glycosylation, in 2017 (Van Damme et al, PMID: 28065471). ATP6V1A-CDG is characterized by the features of cutis laxa (wrinkly, inelastic, droopy skin), redundant skin, typical mask-like facial appearance, muscular hypotonia, cardiac abnormalities, and glycosylation and Golgi defects.
Variants in ATP6V1A have been reported in individuals with the following disease entities in OMIM: Cutis laxa, autosomal recessive, type IID (MIM# 617403) and Developmental and epileptic encephalopathy 93 (MIM# 618012). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the molecular mechanism), phenotype, and inheritance pattern for these two disease entities. Therefore, the two disease entities have remained split. The split curation for Developmental and epileptic encephalopathy 93 (MIM# 618012) may be curated by another ClinGen GCEP. The disease entity in the current curation (Cutis laxa, autosomal recessive, type IID (MIM# 617403) will be renamed as ATP6V1A-CDG based on expert opinion and current naming convention.
Five variants (4 missense, 1 nonsense) that have been reported in 5 probands in 2 publications are included in this curation (Van Damme et al, 2017, PMID: 28065471; Vogt et al, 2021, PMID: 33320377) (Genetic evidence, 3.5 points).
This gene-disease relationship is also supported by experimental evidence, including the biochemical function of the gene product. encodes the catalytic A subunit of the V1 domain of V-ATPase. Variants in genes encoding other subunits of V-ATPase (ATP6V0A2,* ATP6V1E1*) have been implicated in causing similar clinical features. Specifically, the clinical validity classification for ATP6V0A2 with CDG has been classified as definitive by the ClinGen CDG GCEP. In addition, studies on skin biopsy samples and cultured fibroblasts from affected individuals show disruption of vesicular trafficking and abnormalities of elastic fibers and the extracellular matrix, consistent with the connective tissue features observed in patients (Van Damme et al, 2017, PMID: 28065471) (Experimental evidence: 2.5 points)
In summary, there is limited evidence supporting the relationship between* ATP6V1A* and ATP6V1A-CDG (also known as autosomal recessive cutis laxa 2D). This classification was approved by the ClinGen Congenital Disorders of Glycosylation Gene Curation Expert Panel on April 3, 2024 (SOP version 10).