ArticleGenetics in medicine : official journal of the American College of Medical Genetics2021
Reassessment of causality of ABCC6 missense variants associated with pseudoxanthoma elasticum based on Sherloc.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 28 citations in OpenAlex.
- Nonfamilial Pseudoxanthoma Elasticum: A Case Report With Review of Selected Literature.Clinical case reports · 2026Article
- Multi-State Structural Genomics Enables Large-Scale, Mechanistic, and Context-Specific Classification of ABCC6 Genetic Variants Implicated in Calcification Diseases.International journal of molecular sciences · 2026Article
- Observational
- Article
- Pediatric ABCC6 deficiency: a genotypic and phenotypic analysis.Orphanet journal of rare diseases · 2025Review
- Non-Invasive Skin Imaging of Pseudoxanthoma Elasticum Using Dynamic Optical Coherence Tomography: Insights from a Case-Control Study.Dermatology practical & conceptual · 2025Article
- Valvulopathies and Genetics: Where are We?Reviews in cardiovascular medicine · 2024Review
- Clinical and Molecular Characterization of a Patient with Generalized Arterial Calcification of Infancy Caused by RareJournal of personalized medicine · 2023Article
- Inorganic Pyrophosphate Plasma Levels Are Decreased in Pseudoxanthoma Elasticum Patients and Heterozygous Carriers but Do Not Correlate with the Genotype or Phenotype.Journal of clinical medicine · 2023Article
- A new enzymatic assay to quantify inorganic pyrophosphate in plasma.Analytical and bioanalytical chemistry · 2023Article
- The pathogenic c.1171A>G (p.Arg391Gly) and c.2359G>A (p.Val787Ile) ABCC6 variants display incomplete penetrance causing pseudoxanthoma elasticum in a subset of individuals.Human mutation · 2022Article
- Serum Calcification Propensity T50 Associates with Disease Severity in Patients with Pseudoxanthoma Elasticum.Journal of clinical medicine · 2022Article
- Functional Assessment of Missense Variants in the ABCC6 Gene Implicated in Pseudoxanthoma Elasticum, a Heritable Ectopic Mineralization Disorder.The Journal of investigative dermatology · 2022Article
- Arterial dissections: Common features and new perspectives.Frontiers in cardiovascular medicine · 2022Review
- Genetic heterogeneity of heritable ectopic mineralization disorders in a large international cohort.Genetics in medicine : official journal of the American College of Medical Genetics · 2022Article
- Phenotypic Features and Genetic Findings in a Cohort of ItalianJournal of clinical medicine · 2021Article
- Autofluorescence Imaging of the Skin Is an Objective Non-Invasive Technique for Diagnosing Pseudoxanthoma Elasticum.Diagnostics (Basel, Switzerland) · 2021Article
- Rare Modifier Variants Alter the Severity of Cardiovascular Disease in Pseudoxanthoma Elasticum: Identification of Novel Candidate Modifier Genes and Disease Pathways Through Mixture of Effects Analysis.Frontiers in cell and developmental biology · 2021Article
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposePseudoxanthoma 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.
methodsWe used a systematic approach for interpretation of 271 previously reported and 15 novel ABCC6 missense variants, based on the semiquantitative classification system Sherloc.
resultsOnly 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%.
conclusionBesides 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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