Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Jan;23(1):131-139.
doi: 10.1038/s41436-020-00945-6. Epub 2020 Sep 2.

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

Shana Verschuere  1   2 , Nastassia Navassiolava  3 , Ludovic Martin  3 , Pasi I Nevalainen  4 , Paul J Coucke  1   2 , Olivier M Vanakker  5   6
Affiliations
Free article

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

Shana Verschuere et al. Genet Med. 2021 Jan.
Free article

Abstract

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.

PubMed Disclaimer

References

    1. Vanakker OM, et al. Novel clinico-molecular insights in pseudoxanthoma elasticum provide an efficient molecular screening method and a comprehensive diagnostic flowchart. Hum Mutat. 2008;29:205. - DOI
    1. Pfendner EG, et al. Mutation detection in the ABCC6 gene and genotype-phenotype analysis in a large international case series affected by pseudoxanthoma elasticum. J Med Genet. 2007;44:621–628. - DOI
    1. Bergen AAB, et al. Mutations in ABCC6 cause pseudoxanthoma elasticum. Nat Genet. 2000;25:228–231. - DOI
    1. Le Saux O, et al. Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum. Nat Genet. 2000;25:223–227. - DOI
    1. Ringpfeil F, Lebwohl MG, Christiano AM, Uitto J. Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter. Proc Natl Acad Sci U S A. 2000;97:6001–6006. - DOI

Publication types

Substances

LinkOut - more resources