An Alternate Explanation

TO THE EDITOR:

In their Clinical Problem-Solving case, Alsaigh et al. (April 6 issue)¹ describe a man in whom they diagnosed arterial calcification caused by deficiency of CD73 (ACDC), which was attributed to the homozygous NT5E variant c.1126A→G p.(Thr376Ala).² We think this variant should be assessed with caution. The application of the guidelines of the American College of Medical Genetics and Genomics for variant classification³ is standard practice when describing a possible disease-causing variant, and on the basis of population frequency, the c.1126A→G variant would be classified as benign.

Previously described patients with ACDC⁴ all had variants with an allele frequency of less than 1×10−4 in the Genome Aggregation Database (gnomAD), and the biallelic c.1126A→G variant had been observed in their asymptomatic family members.⁵ The incidence of homozygosity for this variant in gnomAD subpopulations ranges from 36 to 87%. Homozygotes for the reference allele constitute a smaller percentage, ranging from 0.45 to 17%. The c.1126A→G variant is also the major allele in 22 other population databases.⁶ Additional research is needed to determine whether the c.1126A→G variant has any role in human disease, but the large number of homozygotes in public databases suggests that this variant is not a cause of the rare disease ACDC.