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



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.


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


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%.


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.

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Fig. 1: Genomic organization, transcript, and protein structure of ABCC6.
Fig. 2: Approach for classification of ABCC6 missense variants.
Fig. 3: Classification results based on Sherloc.
Fig. 4: Comparison of classification results between Sherloc and American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG-AMP) or ClinVar or Leiden Open Variation Database (LOVD).


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This study was supported by a Methusalem grant (BOFMET2015000401) from Ghent University. O.M.V. is a Senior Clinical Investigator of the research Foundation–Flanders (Belgium).

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Correspondence to Olivier M. Vanakker MD, PhD.

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Verschuere, S., Navassiolava, N., Martin, L. et al. Reassessment of causality of ABCC6 missense variants associated with pseudoxanthoma elasticum based on Sherloc. Genet Med (2020).

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  • pseudoxanthoma elasticum
  • ABCC6
  • genetic variation
  • pathogenic variant
  • variant interpretation