ClinVar: improvements to accessing data

Landrum, Melissa; Chitipiralla, Shanmuga; Brown, Garth; Chen, Chao; Gu, Baoshan; Hart, Jennifer; Hoffman, Douglas; Jang, Wonhee; Kaur, Kuljeet; Liu, Chunlei; Lyoshin, Vitaly; Maddipatla, Zenith; Maiti, Rama; Mitchell, J.K.; O’Leary, Nuala; Riley, George F.; Shi, Wenyao; Zhou, George; Schneider, Valérie; Maglott, Donna; Holmes, J. Bradley; Kattman, B

doi:10.1093/nar/gkz972

Cited by 650 publications

(620 citation statements)

References 15 publications

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“…It is 18.3 kb long, contains 20 exons, and encodes 952 amino acids. At present, more than 900 variants are registered in the ClinVar [16] or Pompe disease GAA variant databases [17], and the numbers are increasing. About two-thirds of these variants are classified by clinical significance and the other third of the variants are VOUS.…”

Section: Gaa Gene Analysismentioning

confidence: 99%

Newborn Screening for Pompe Disease

Sawada

Kido

Nakamura

2020

IJNS

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Glycogen storage disease type II (also known as Pompe disease (PD)) is an autosomal recessive disorder caused by defects in α-glucosidase (AαGlu), resulting in lysosomal glycogen accumulation in skeletal and heart muscles. Accumulation and tissue damage rates depend on residual enzyme activity. Enzyme replacement therapy (ERT) should be started before symptoms are apparent in order to achieve optimal outcomes. Early initiation of ERT in infantile-onset PD improves survival, reduces the need for ventilation, results in earlier independent walking, and enhances patient quality of life. Newborn screening (NBS) is the optimal approach for early diagnosis and treatment of PD. In NBS for PD, measurement of AαGlu enzyme activity in dried blood spots (DBSs) is conducted using fluorometry, tandem mass spectrometry, or digital microfluidic fluorometry. The presence of pseudodeficiency alleles, which are frequent in Asian populations, interferes with NBS for PD, and current NBS systems cannot discriminate between pseudodeficiency and cases with PD or potential PD. The combination of GAA gene analysis with NBS is essential for definitive diagnoses of PD. In this review, we introduce our experiences and discuss NBS programs for PD implemented in various countries.

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Section: Gaa Gene Analysismentioning

confidence: 99%

Newborn Screening for Pompe Disease

Sawada

Kido

Nakamura

2020

IJNS

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“…The frameshift deletion in germline state is herein reported in a GC, while previously it has been described only in the somatic neoplastic cells (COSV55727175) of tumors from the esophagus and of the large intestine. The variant described in this manuscript was submitted to the Leiden Open Variant Database (LOVD, ID number 00276019) ( ) and reported in ClinVar SUB6906561 [ 8 ].…”

Section: Resultsmentioning

confidence: 99%

Family’s History Based on the CDH1 Germline Variant (c.360delG) and a Suspected Hereditary Gastric Cancer Form

Caggiari

Fornasarig

Zorzi

et al. 2020

IJMS

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Hereditary diffuse gastric cancer (HDGC) is a cancer susceptibility syndrome caused by germline pathogenic variant in CDH1, the gene encoding E-cadherin. The germline loss-of-function variants are the only proven cause of the cancer syndrome HDGC, occurring in approximately 10–18% of cases and representing a helpful tool in genetic counseling. The current case reports the family history based on a CDH1 gene variant, c.360delG, p.His121Thr in a suspected family for hereditary gastric cancer form. This frameshift deletion generates a premature stop codon at the amino acid 214, which leads to a truncated E-cadherin protein detecting it as a deleterious variant. The present study expands the mutational spectra of the family with the CDH1 variant. Our results highlight the clinical impact of the reported CDH1 variant running in gastric cancer families.

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“…In addition, MendelVar cross-references input genomic intervals against ClinVar (Landrum et al, 2019) In MendelVar, HPO terms were collected first from OMIM, and then complemented with Orphanet, Decipher DDG2P and official HPO annotations, which altogether contributed HPO terms to 410 diseases with no previous HPO terms in OMIM. Similarly, DO terms were first mined from OMIM, followed by Orphanet and the official DO annotation.…”

Section: Integration Of Mendelvar Data Sourcesmentioning

confidence: 99%

MendelVar: gene prioritization at GWAS loci using phenotypic enrichment of Mendelian disease genes

Sobczyk

Gaunt

Paternoster

2020

Preprint

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Gene prioritisation at GWAS loci necessities careful assembly and examination of different types of molecular evidence to arrive at a set of plausible candidates. In many human traits, common small-effect mutations may subtly dysregulate the function of the very same genes which are impacted by rare, large-effect mutations causing Mendelian disease of similar phenotype. However, information on gene-Mendelian disease associations, rare pathogenic mutations driving the disease, and the disease phenotype ontology is dispersed across many data sources and does not integrate easily with enrichment analysis.MendelVar is a new webserver facilitating transfer of knowledge from Mendelian disease research into interpretation of genetic associations from GWAS of complex traits.MendelVar allows querying of pre-defined or LD-determined genomic intervals against a comprehensive integrated database to find overlap with genes linked to Mendelian disease. Next, MendelVar looks for enrichment of any Human Phenotype Ontology, DiseaseOntology and other ontology/pathway terms associated with identified Mendelian genes. In addition, MendelVar provides a list of all overlapping pathogenic and likely pathogenic variants for Mendelian disease sourced from ClinVar. Inclusion of information obtained from MendelVar in post-GWAS gene annotation pipelinescan strengthen the case for causal importance of some genes. Moreover, as genes with Mendelian disease evidence may make for more successful drug targets, this may be particularly useful in drug discovery pipelines. Taking GWAS summary statistics for malepattern baldness, intelligence and atopic dermatitis, we demonstrate the use of MendelVar in prioritizing candidate genes at these loci which are linked to relevant enriched ontology terms. MendelVar is freely available at https

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ClinVar: improvements to accessing data

Cited by 650 publications

References 15 publications

Newborn Screening for Pompe Disease

Newborn Screening for Pompe Disease

Family’s History Based on the CDH1 Germline Variant (c.360delG) and a Suspected Hereditary Gastric Cancer Form

MendelVar: gene prioritization at GWAS loci using phenotypic enrichment of Mendelian disease genes

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