ClinVar: improving access to variant interpretations and supporting evidence

By M. Landrum, Jennifer M. Lee, M. Benson, Garth R. Brown, Chen Chao, Shanmuga Chitipiralla, Baoshan Gu, Jennifer Hart, Douglas Hoffman, W. Jang and 12 more. 2017

3,690 citations recorded by the source corpus.

Abstract ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) is a freely available, public archive of human genetic variants and interpretations of their significance to disease, maintained at the National Institutes of Health. Interpretations of the clinical significance of variants are submitted by clinical testing laboratories, research laboratories, expert panels and other groups. ClinVar aggregates data by variant-disease pairs, and by variant (or set of variants). Data aggregated by variant are accessible on the website, in an improved set of variant call format files and as a new comprehensive XML report. ClinVar recently started accepting submissions that are focused primarily on providing phenotypic information for individuals who have had genetic testing. Submissions may come from clinical providers providing their own interpretation of the variant (‘provider interpretation’) or from groups such as patient registries that primarily provide phenotypic information from patients (‘phenotyping only’). ClinVar continues to make improvements to its search and retrieval functions. Several new fields are now indexed for more precise searching, and filters allow the user to narrow down a large set of search results.

Subfields: Cancer Research, Genetics, Molecular Biology

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Citations in the corpus

15 years of PhosphoSitePlus®: integrating post-translationally modified sites, disease variants and isoforms (2018, background): “Proteins associated with inherited diseases have been retrieved from ClinVar (16), which lists 3265 proteins with missense mutations that are ‘pathogenic’ or ‘pathogenic/likely pathogenic’ in their July 2018 release.”
ClinVar: improvements to accessing data (2019, methodology): “Similar to ClinVarFullRelease (12), the variant-centric XML is generated and archived monthly.”
Transcript expression-aware annotation improves rare variant discovery and interpretation (2019, methodology): “0, and ClinVar variants were filtered to those marked as pathogenic, with no conflicts, and reviewed with at least one star status.”
GENCODE: reference annotation for the human and mouse genomes in 2023 (2022, background): “In addition, we have annotated 58 MANE Plus Clinical transcript models, which are alternatively spliced transcripts within genes where a single transcript does not support the description of all known and likely pathogenic variants in ClinVar(14).”
Accurate proteome-wide missense variant effect prediction with AlphaMissense (2023, methodology): “We avoid training directly on clinically curated labels to mitigate such issues and enable faithful evaluation on diverse benchmarks, including the held-out test set of annotated missense variants in ClinVar (30), de novo variants from patients with rare developmental Model inputs”
Artificial intelligence in clinical and genomic diagnostics (2019, background): “Prima-teAI substantially exceeded the performance of other variant pathogenicity prediction tools in differentiating benign and pathogenic de-novo mutations in candidate developmental disorder genes, and in reproducing prior knowledge in Clinvar [60].”
Missense variants causing Wiedemann-Steiner syndrome preferentially occur in the KMT2A-CXXC domain and are accurately classified using AlphaFold2 (2022, neutral): “To increase our power, we chose to include ClinVar variants labeled as Pathogenic, Likely Pathogenic, or Variants of Uncertain Significance (VUS), and filtered them using the phred-like CADD scores, acquired from Ensembl Variant Effect Predictor (VEP) [16].”
Mutation severity spectrum of rare alleles in the human genome is predictive of disease type (2019, methodology): “We obtained SAVs that were classified as likely pathogenic from the ClinVar [33] and UniProt database.”