Probing the functional consequence and clinical relevance of CD320 p.E88del, a variant in the transcobalamin receptor gene

Faith Pangilinan, David Watkins, David Bernard, Yue Chen, Ningzheng Dong, Qingyu Wu, Hatice Ozel-Abaan, Manjit Kaur, Michele Caggana, Mark Morrissey, Marilyn L. Browne, James L. Mills, Carol Van Ryzin, Oleg Shchelochkov, Jennifer Sloan, Charles P. Venditti, Kyriakie Sarafoglou, David S. Rosenblatt, Denise M. Kay, Lawrence C. Brody

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


The biological and clinical significance of the p.E88del variant in the transcobalamin receptor, CD320, is unknown. This allele is annotated in ClinVar as likely benign, pathogenic, and of uncertain significance. To determine functional consequence and clinical relevance of this allele, we employed cell culture and genetic association studies. Fibroblasts from 16 CD320 p.E88del homozygotes exhibited reduced binding and uptake of cobalamin. Complete ascertainment of newborns with transiently elevated C3 (propionylcarnitine) in New York State demonstrated that homozygosity for CD320 p.E88del was over-represented (7/348, p < 6 × 10 -5 ). Using population data, we estimate that ~85% of the p.E88del homozygotes born in the same period did not have elevated C3, suggesting that cobalamin metabolism in the majority of these infants with this genotype is unaffected. Clinical follow-up of 4/9 homozygous individuals uncovered neuropsychological findings, mostly in speech and language development. None of these nine individuals exhibited perturbation of cobalamin metabolism beyond the newborn stage even during periods of acute illness. Newborns homozygous for this allele in the absence of other factors are at low risk of requiring clinical intervention, although more studies are required to clarify the natural history of various CD320 variants across patient populations.

Original languageEnglish (US)
Pages (from-to)1124-1141
Number of pages18
JournalAmerican Journal of Medical Genetics, Part A
Issue number4
StatePublished - Apr 2022

Bibliographical note

Funding Information:
The authors wish to express their appreciation to the research participants. The authors are also grateful to Tracy Klug and Laura Hayes for providing newborn screening data for Missouri and Arkansas, respectively; Emily McGrath and Adam Gearhart at the New York State Newborn Screening Program for technical assistance; and Sandra Richardson at the New York State Birth Defects Registry for data management. Sources of funding include the Intramural Research Program of the National Human Genome Research Institute, the National Institute of Child Health and Human Development (N01‐DK‐7‐3431), Canadian Institutes for Health Research (CIHR) Project Grant 148661, and the Hess B. and Diane Finestone Laboratory in Memory of Jacob and Jenny Finestone. Eunice Kennedy Shriver

Funding Information:
Canadian Institutes for Health Research, Grant/Award Number: Project Grant 148661; Eunice Kennedy Shriver National Institute of Child Health and Human Development, Grant/Award Number: N01‐DK‐7‐3431; Hess B.and Diane Finestone Laboratory in Memory of Jacob and Jenny Finestone; National Human Genome Research Institute Intramural Research Program Funding information

Publisher Copyright:
© 2022 Wiley Periodicals LLC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.


  • C3-acylcarnitine
  • CD320
  • cobalamin
  • newborn screening
  • transcobalamin receptor
  • transcobalamin receptor deficiency


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