Submission Details

PMM2 was first reported in relation to autosomal recessive hyperinsulinemic hypoglycemia with polycystic kidney disease (HIPKD) in 2017 (Cabezas et al., 2017; PMID: 28373276). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found sufficient differences in molecular mechanism and phenotype to consider HIPKD separately. The HIPKD phenotype is caused specifically by the PMM2 promoter variant c.-167G>T, either in a homozygous state or in trans with another pathogenic variant in PMM2, while congenital disorder of glycosylation, type 1A (CDG1A) is caused by other recessive mutant genotypes in PMM2. Therefore, the following disease entities have been split into two disease entities: autosomal recessive HIPKD and autosomal recessive congenital disorders of glycosylation, type 1A (CDG1A; OMIM: 212065); CDG1A has been curated separately. Eight variants (1 promoter; c.-167G>T and 7 missense) that have been reported in over 20 probands in 5 publications (PMIDs: 28373276, 32841164, 33532864, 34055813, 36412659; Fundación Puigvert internal data) are included in this curation. The mechanism of pathogenicity is reported to be decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143. This gene-disease relationship is also supported by experimental evidence (expression-level evidence, biochemical functional evidence, functional alteration evidence; GTEx/Humphrey’s Lab Expression data, PMIDs: 28373276, 35896117). In summary, there is Moderate evidence supporting the relationship between the PMM2 c.-167G>T promoter variant and autosomal recessive HIPKD. There is limited evidence supporting the relationship of any other variant causing a kidney-specific phenotype. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date 2/28/2024 (SOP Version 10).