Reassessment of causality of ABCC6 missense variants associated with pseudoxanthoma elasticum based on Sherloc

Genet Med. 2021 Jan;23(1):131-139. doi: 10.1038/s41436-020-00945-6. Epub 2020 Sep 2.


Purpose: Pseudoxanthoma elasticum (PXE) is a heritable disorder affecting elastic fibers in the skin, eyes, and cardiovascular system. It is caused by biallelic pathogenic variants in the ABCC6 gene. To date, over 300 ABCC6 variants are associated with PXE, more than half being missense variants. Correct variant interpretation is essential for establishing a direct link between the variant and the patient's phenotype and has important implications for diagnosis and treatment.

Methods: We used a systematic approach for interpretation of 271 previously reported and 15 novel ABCC6 missense variants, based on the semiquantitative classification system Sherloc.

Results: Only 35% of variants were very likely to contribute directly to disease, in contrast to reported interpretations in ClinVar, while 59% of variants are currently of uncertain significance (VUS). Subclasses were created to distinguish VUS that are leaning toward likely benign or pathogenic, increasing the number of (likely) pathogenic ABCC6 missense variants to 47%.

Conclusion: Besides highlighting discrepancies between the Sherloc, American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP), ClinVar, and Leiden Open Variation Database (LOVD) classification, our results emphasize the need for segregation analysis, functional assays, and detailed evidence sharing in variant databases to reach a confident interpretation of ABCC6 missense variants and subsequent appropriate genetic and preconceptual counseling.

Keywords: ABCC6; genetic variation; pathogenic variant; pseudoxanthoma elasticum; variant interpretation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Multidrug Resistance-Associated Proteins / genetics
  • Mutation
  • Mutation, Missense
  • Phenotype
  • Pseudoxanthoma Elasticum* / diagnosis
  • Pseudoxanthoma Elasticum* / genetics


  • ABCC6 protein, human
  • Multidrug Resistance-Associated Proteins