DEAFNESS VARIATION DATABASE

Classification criteria

DVD categorization is based on the following criteria:

MORL research and clinical data

As we continue to evaluate patients with OtoSCOPE®, we document that information within DVD to improve our variant calling abilities for future patients.

Minor allele frequency (MAF)

In previous studies we have determined that in most genes associated with hearing loss, variants with a MAF of ≥0.005 (0.5%) are likely to be benign. Genes that do not adhere to this cutoff include GJB2, SLC26A4, PCDH15, and MYO15A. In addition, in small populations, certain variants may be observed with higher MAFs. MAFs are not available for all variants.

Literature

Available information from ClinVar and/or the published literature on PubMed are considered when available.

Computational predictions

The DVD uses 6 computational methods (PhyloP, SIFT, LRT, MutationTaster, PolyPhen HDIV, and GERP) to assess functional significance and conservation of missense variants. A score of at least (a.) 4 out of 6 or (b.) 3 out of 5 is generally considered to indicate that a variant is more likely to be pathogenic than benign, but pathogenicity predictions are used only as a guideline to aid interpretation and are not used solely to determine pathogenicity. Pathogenicity predictions are not available for all variants.

Likely protein effect

Many genes are known to cause phenotypes in knockout model animals or when null alleles are observed in humans. Variants causing a frameshift/stop-gain within these genes are likely to be pathogenic in the autosomal recessive state. Curation of these variants is ongoing, and therefore you may find such variants currently labeled in the DVD as VUSs or benign.

Variant classifications

These criteria are specific for non-syndromic hearing loss only and may not be applicable to other diseases or conditions. Phenotypes that are not deafness-related are not curated with the same stringency as other variants.

Consideration of these criteria result in these variant types:

Benign
Previously reported benign variants or variants with a MAF ≥ 0.005. There are gene-specific exceptions to this rule including alleles of GJB2, SLC26A4, PCDH15 and MYO15A. Classifications with an asterisk (*) are based on the methods described by Shearer AE, et al 2014. This label means that the variant has been previously reported as pathogenic, but we found its MAF to be too high to be consistent with non-syndromic hearing loss. In other words, the variant was re-categorized from pathogenic to benign.
Likely benign
Classified as such by MORL, ClinVar, and/or literature when available; otherwise prediction-based.
Likely pathogenic
Classified as such by MORL, ClinVar, and/or literature when available.
Pathogenic
Classified as such by MORL, ClinVar, and/or literature when available.
Variant of unknown significance (VUS)
All variants that do not fall into one of the above categories.