Semi-automation of ClinVar variants
Of 4948 ClinVar variants in 142 deafness-related genes, VIP-HL achieved
an overall variant interpretation concordance of 88.0% (4353/4948). The
concordant interpretations were 57.1% (376/658) in P/LP variants,
93.6% (3083/3295) in B/LB variants, and 89.8% (894/995) in VUS
variants, respectively (Table 2). The lower concordance in P/LP variants
could be expained that VIP-HL is a semi-automated tool and only
automated 13 out of 24 ACMG/AMP rules.
Of note, VIP-HL generated three P/LP classifications versus B/LB
compared to ClinVar.The first one was
NM_153676.3(USH1C ):c.2547-1G>T. It was submitted as
likely benign in ClinVar, whereas VIP-HL assigned PVS1 and PM2, leading
to a likely pathogenic classification. Manual curation revealed that
this splicing variant affected an exon in transcript NM_153676.3 with
no detectable expression based on the Genotype-Tissue Expression (GTEx)
database (GTEx Consortium, 2017). Thus, this variant should be
classified as benign/likely benign. This example highlights the need for
including information about the most biologically relevant transcripts
in VIP-HL for accurate clinical variant interpretation (DiStefano et
al., 2018).
The other two discrepant variants were synonymous
(NM_206933.3(USH2A ):c.949C>A (p.Arg317=) and
NM_022124.6(CDH23 ):c.7362G>A (p.Thr2454=). Both
were assigned likely benign classifications by VIP-HL due to the
activation of BP4 and BP7. Specifically,
NM_206933.3:c.949C>A was submitted as a pathogenic variant
in ClinVar. This variant led to abnormal splicing and a premature
termination codon (Vaché et al., 2010), strongly supporting its
pathogenic classification. As shown below, our VIP-HL user interface
will enable curators to manually activate codes for functional studies
to avoid such possible misclassifications. The second variant,
NM_022124.6(CDH23 ):c.7362G>A, was submitted as
likely pathogenic. No supporting RNA/functional, case-level or
segregation studies were provided to support this classification. Since
the actual effect of this sequence change is still unknown, a likely
benign classification may be more appropriate for this case.
Of 4948 ClinVar variants, the most utilized rules were
population-related, spanning PM2, BA1, BS1, BS2 and their modified
strength levels (supporting through very strong; Figure 2). BP4 and BP7
are also frequently used because 33.5% (1657/4948) deafness-related
variants with ClinVar star 2+ were synonymous variants. As expected, the
pathogenic criteria were enriched in pathogenic/likely pathogenic
variants, whereas benign criteria were enriched in benign/likely benign
variants (Figure 2).