Case Z arr [GRCh37] 19p13.11(18291753_18311626) x3 - PowerPoint Presentation

1. Case Zarr[GRCh37] 19p13.11(18291753_18311626) x32-month-old female with Tetralogy of Fallot; inheritance unknown

2. Clinical informationarr [GRCh37] 19p13.11(18291753_18311626) x3 2-month-old female with Tetralogy of FallotInheritance information not availableFor the sake of example, assume the size of this CNV is one that is reliably detected by your platform and meets your reporting requirements.Use the GAIN scoring metric

3. Section 1: Initial Assessment of Genomic ContentContains protein-coding genes (Category 1A)0 points, continue evaluationGenes InvolvedOur caseTotal: 0 points

4. Section 2: Evaluation of Known Dosage Sensitive (or Benign) Genes/RegionsNo known dosage sensitive or benign genes/genomic regions.0 points, continue evaluationTotal: 0 points

5. Section 3: Gene CountContains 2 protein-coding genes (Category 3A)0 points, continue evaluationTotal: 0 points

6. Section 4: Detailed Evaluation of Genomic ContentThere is a similarly-sized duplication in the DGV Gold Standard Dataset – let’s look into this further.

7. This frequency is >> the 1% threshold in category 4O – should we assign -1 points and classify this CNV as benign?

8. Check the number of variants/number of samples tested before automatically classifying something as Benign based on population frequency.In this instance, the frequency of 12.9% is based on 4 observations across 31 samples tested.

9. PMID: 30311383

10. Can we find any other information about this area of the genome?

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12. How frequent is too frequent for your phenotype?The 1% threshold for category 4O is a general guideFor some phenotypes, this will be too highIn some situations, this may be too lowFor certain phenotypes, enough information may be available to calculate the maximum expected allele frequency of a disease-causing variant in the general populationUse the CardioDB Allele Frequency calculatorTo be conservative (and end up with the most generous credible allele frequency/allele count), select:The highest (i.e., most frequent) reported disease prevalenceThe most frequent single genetic causeThe lowest credible estimate of penetrance

13. http://cardiodb.org/allelefrequencyapp/Estimated prevalence of ToF from NORD (https://rarediseases.org/rare-diseases/tetralogy-of-fallot/)Per OMIM (#187500), the most common genetic cause of ToF is the 22q11.2 deletion, found in ~7% of patients (Rauch et al. 2010). The allelic heterogeneity is set at 0.07 to indicate that no single variant should be more frequent than the 22q11.2 deletion. See the directions at the bottom of the web page for more information on how to utilize these fields.Default penetrance set at 0.5.Used number of samples tested from gnomAD SV.Allele frequency of our comparable gnomAD variant: 0.003643Allele Count: 79 (and 4 homozygotes)PMID: 28518168Whiffin et al. 2017

14. What if we changed the penetrance?Allele frequency of our comparable gnomAD variant: 0.003643Allele Count: 79 (and 4 homozygotes)

15. What if we changed the penetrance?Allele frequency of our comparable gnomAD variant: 0.003643Allele Count: 79 (and 4 homozygotes)

16. How should we score this variant?Even though the overall frequency in the larger sample isn’t 1%, in this scenario, it still makes sense to assign -1 points.The frequency in the East Asian population was almost 3% with over 2000 alleles tested.Even if we did not have this information, given the rarity of our phenotype, the overall frequency of the comparable variant observed in the larger sample (gnomAD SV) is too high to make sense as possible cause for Tetralogy of Fallot (using the Cardiodb calculator)The high frequency from DGV alone would not be enough to warrant -1 due to the sample size for that particular variant.Note that there are many other variants in the DGV gold standard dataset that do have appropriately high sample sizes.Always check this information!To complete the evaluation, do a literature search to ensure:No reports of phenotype associated with duplication of MPV17L2No reports of phenotype associated with potential loss of RAB3AAssuming none, this CNV can be classified as Benign

17. Today’s Attendance URL and QR code:https://tinyurl.com/AttendanceFeb27