Classification criteria
DVD classifications integrate multiple lines of evidence as detailed in our flagship paper Genomic Landscape and Mutational Signatures of Deafness-Associated Genes
MORL research and clinical data
Ongoing OtoSCOPE® testing contributes case-level evidence that informs variant interpretation. Curated observations are incorporated into the DVD to improve future classifications.
Population 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.
Founder effects and small populations can yield higher MAFs for pathogenic alleles; these contexts are considered during review.
MAFs are not available for all variants.
Literature and external databases
Case-level evidence from ClinVar and/or peer-reviewed literature (PubMed) is incorporated 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.
Computational predictions are supportive only and are not used as the sole basis for a classification.
Scores are not available for all variants.
* Likely protein effect: In genes where loss of function is an established disease mechanism, frameshift/stop-gain/splice variants 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
Classifications are updated as new evidence emerges. Users should consult the most current release and exercise clinical judgment.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:
- Pathogenic
- Definitive evidence for pathogenicity. Classified as such by MORL based on integrated evidence, ClinVar, and/or literature when available.
- Likely pathogenic
- Strong but no definitive evidence for pathogenicity. Classified as such by MORL based on integrated evidence, ClinVar, and/or literature when available.
- 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, indicating a variant previously reported as pathogenic but re-categorized as benign due to an MAF inconsistent with nonsyndromic hearing loss.
- Likely benign
- Classified as such by MORL, ClinVar, and/or literature when available; otherwise prediction-based.
- Variant of unknown significance (VUS)
- All variants that do not fall into one of the above categories.
*Phenotypes that are not deafness-related are not curated with the same stringency as other variants.