Submission Details

CD320 was first reported in relation to autosomal recessive methylmalonic acidemia due to transcobalamin receptor defect in 2010 (Quadros et al, PMID: 20524213).

CD320 encodes the transcobalamin receptor, which mediates the cellular uptake of vitamin B12 (cobalamin, Cbl). In mammalian cells, methylCbl is a cofactor for methionine synthase, which converts homocysteine to methionine, and 5′-deoxy-adenosylCbl is a cofactor for methylmalonyl CoA mutase, which converts methylmalonyl CoA to succinyl CoA. Cbl deficiency, due to various defects in Cbl transport and metabolism, can result in homocysteinemia due to inhibition of the methionine synthase pathway, and methylmalonic acidemia (MMA) due to inhibition of the mutase pathway.

Genetic evidence: Quadros et al, 2010 (PMID: 20524213) identified a homozygous in frame deletion in CD320 (NM_016579.3:c.262_264delGAG (p.Glu88del) in a child with elevated C3 (propionylcarnitine) identified by newborn screening, who had moderately elevated methylmalonic acid (MMA) that later normalized. At least 16 cases homozygous for the same variant and with transiently elevated C3, elevated MMA, and elevated homocysteine have been reported (Quadros et al, 2010, PMID: 20524213; Karth et al, 2012, PMID: 22819238; Hannah-Shmouni et al, 2018, PMID: 29663633; Pappas et al, 2022, PMID: 34978764; Pangilinan et al, 2022, PMID: 35107211). Except for one individual from a consanguineous family who presented with bilateral retinal artery occlusions at 7 weeks of age (Karth et al, 2012, PMID: 22819238), p.Glu88del homozygotes have been identified on newborn screen, and typically have had no major health or developmental concerns (Pappas et al, 2022, PMID: 34978764; Pangilinan et al, 2022, PMID: 35107211).

In a study of infants undergoing newborn screen in New York state, 7/348 infants with transient elevation of C3 were homozygous for CD320 p.Glu88del, while none of the 380 controls were homozygous for this variant (Pangilinan et al, 2022, PMID: 35107211). This data was scored as a case-control study (4 points). Additional genetic evidence included reports of individuals with p.Glu88del in compound heterozygosity with another variant (Pappas et al, 2022, PMID: 34978764; Pangilinan et al 2022, PMID: 35107211). The mechanism of pathogenicity appears to be loss of function.

Experimental evidence: This gene-disease relationship is supported by experimental evidence including the biochemical function of the transcobalamin receptor (Quadros et a;, PMID: 18779389; Lai et al, 2011, PMID: 21377459; Alam et al, 2016, PMID: 27411955; Gick et al, 2020, PMID: 32898552); reduced holotranscobalamin binding and uptake, and reduced activity of cobalamin-dependent enzymes methylmalonyl-CoA mutase and methionine synthase in fibroblasts from patients with variants in CD320 (Pangilinan et al 2022, PMID: 35107211); and the biochemical and clinical findings in Cd320 knock-out mice which recapitulate observations in human patients (Lai et al, 2013, PMID: 23430977; Arora et al, 2017, PMID: 28545069; Bernard et al, 2018, PMID: 30124850). Additional experimental evidence is available in the literature but the maximum points (6 points) has been reached.

In summary, there is definitive evidence to show that biallelic variants in CD320 can result in methylmalonic acidemia due to transcobalamin receptor defect. The most common cause is homozygosity for CD320 p.Glu88del which has been associated with transiently elevated C3 (picked up on newborn screen), and variable elevations of MMA and homocysteine that normalize upon hydroxocabalmin treatment (Pappas et al, 2022, PMID: 34978764). Data indicates that about 85% of these individuals may not be identified, and that the condition is probably benign, although further studies are needed to assess any longterm health effects (Pappas et al, 2022, PMID: 34978764; Pangilinan et al, 2022, PMID: 35107211). This classification was approved by the General Inborn Errors of Metabolism GCEP on Sept. 23, 2022.