ClinVar database of global familial hypercholesterolemia-associated DNA variants

Abstract

Accurate and consistent variant classification is imperative for incorporation of rapidly developing sequencing technologies into genomic medicine for improved patient care. An essential requirement for achieving standardized and reliable variant interpretation is data sharing, facilitated by a centralized open-source database. Familial hypercholesterolemia (FH) is an exemplar of the utility of such a resource: it has a high incidence, a favorable prognosis with early intervention and treatment, and cascade screening can be offered to families if a causative variant is identified. ClinVar, an NCBI-funded resource, has become the primary repository for clinically relevant variants in Mendelian disease, including FH. Here, we present the concerted efforts made by the Clinical Genome Resource, through the FH Variant Curation Expert Panel and global FH community, to increase submission of FH-associated variants into ClinVar. Variant-level data was categorized by submitter, variant characteristics, classification method, and available supporting data. To further reform interpretation of FH-associated variants, areas for improvement in variant submissions were identified; these include a need for more detailed submissions and submission of supporting variant-level data, both retrospectively and prospectively. Collaborating to provide thorough, reliable evidence-based variant interpretation will ultimately improve the care of FH patients.

Keywords: ClinVar; Clinical Genome Resource; familial hypercholesterolemia; variant interpretation.

Figure 1.

Unique FH-associated variants in ClinVar by exonic location and type of variant. Variants in introns are represented in the closest exon. NA, not applicable (variants spanning more than one exon); double variant, single submission with two variants in the same allele; intronic, variants outside +/−15 nucleotides (nts) of intron/exon border; splicing, variants known to affect splicing or variants within +/−15 nts of intron/exon border; indel, insertion or deletion variant; UTR, untranslated region; CNVs, copy number variation.

Figure 1.

Unique FH-associated variants in ClinVar by exonic location and type of variant. Variants in introns are represented in the closest exon. NA, not applicable (variants spanning more than one exon); double variant, single submission with two variants in the same allele; intronic, variants outside +/−15 nucleotides (nts) of intron/exon border; splicing, variants known to affect splicing or variants within +/−15 nts of intron/exon border; indel, insertion or deletion variant; UTR, untranslated region; CNVs, copy number variation.

Figure 1.

Unique FH-associated variants in ClinVar by exonic location and type of variant. Variants in introns are represented in the closest exon. NA, not applicable (variants spanning more than one exon); double variant, single submission with two variants in the same allele; intronic, variants outside +/−15 nucleotides (nts) of intron/exon border; splicing, variants known to affect splicing or variants within +/−15 nts of intron/exon border; indel, insertion or deletion variant; UTR, untranslated region; CNVs, copy number variation.

Figure 2.

Treemap partition of unique FH-associated variants in ClinVar conveying the relative proportions of variant classifications for each variant type. Conflicting classifications are only considered for variants with multiple submissions, defined by the following discordances: Benign/Likely benign + Uncertain significance; Pathogenic/Likely pathogenic + Uncertain significance; Benign/Likely benign + Pathogenic/Likely pathogenic. Double variant, single submission with two variants in the same allele; intronic, variants outside +/−15 nucleotides (nts) of intron/exon border; splicing, variants known to affect splicing or variants within +/−15 nts of intron/exon border; Indel, insertion or deletion variant; CNVs, copy number variation; UTR, untranslated region; P/LP, Pathogenic/Likely pathogenic; B/LB, Benign/Likely benign; VUS, variant of Uncertain Significance.

Figure 2.

Treemap partition of unique FH-associated variants in ClinVar conveying the relative proportions of variant classifications for each variant type. Conflicting classifications are only considered for variants with multiple submissions, defined by the following discordances: Benign/Likely benign + Uncertain significance; Pathogenic/Likely pathogenic + Uncertain significance; Benign/Likely benign + Pathogenic/Likely pathogenic. Double variant, single submission with two variants in the same allele; intronic, variants outside +/−15 nucleotides (nts) of intron/exon border; splicing, variants known to affect splicing or variants within +/−15 nts of intron/exon border; Indel, insertion or deletion variant; CNVs, copy number variation; UTR, untranslated region; P/LP, Pathogenic/Likely pathogenic; B/LB, Benign/Likely benign; VUS, variant of Uncertain Significance.

Figure 2.

Treemap partition of unique FH-associated variants in ClinVar conveying the relative proportions of variant classifications for each variant type. Conflicting classifications are only considered for variants with multiple submissions, defined by the following discordances: Benign/Likely benign + Uncertain significance; Pathogenic/Likely pathogenic + Uncertain significance; Benign/Likely benign + Pathogenic/Likely pathogenic. Double variant, single submission with two variants in the same allele; intronic, variants outside +/−15 nucleotides (nts) of intron/exon border; splicing, variants known to affect splicing or variants within +/−15 nts of intron/exon border; Indel, insertion or deletion variant; CNVs, copy number variation; UTR, untranslated region; P/LP, Pathogenic/Likely pathogenic; B/LB, Benign/Likely benign; VUS, variant of Uncertain Significance.

Figure 3.

Number of unique variants (n=2796) classified by different sets of criteria. For 87 unique variants, no classification was submitted. ACMG/AMP Guidel, American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines (Richards et al., 2015); ACMG/AMP Framew, criteria following the ACMG/AMP framework; ACGS, Association for Clinical Genetic Science Guidelines; Independent, criteria provided not based on ACMG/AMP or ACGS frameworks; No criteria, classification given but the criteria used was not provided.