Table 1:

CNV Interpretation Scoring Metric - Copy Number LOSS

Scoring: • Pathogenic: 0.99 or more points • Likely Pathogenic: 0.90 to 0.98 points • Variant of Uncertain Significance: 0.89 to −0.89 points • Likely Benign: −0.90 to −0.98 points • Benign: −0.99 or fewer points
Section 1: Initial Assessment of Genomic Content
Evidence Type	Evidence	Suggested Points/Case	Max Score
Copy number loss content	1A. Contains protein-coding or other known functionally important elements	0 (Continue Evaluation)	0
	1B. Does NOT contain protein-coding or any known functionally important elements	−0.60	−0.60
Section 2: Overlap with Established/Predicted HI or Established Benign Genes/Genomic Regions (Skip to Section 3 if your copy number loss DOES NOT overlap these types of genes/regions)
Overlap with ESTABLISHED HI genes or genomic regions and consideration of reason for referral	2A. Complete overlap of an established HI gene/genomic region	1.00	1.00
	2B. Partial overlap of an established HI genomic region The observed CNV does NOT contain the known causative gene or critical region for this established HI genomic region OR Unclear if known causative gene or critical region is affected OR No specific causative gene or critical region has been established for this HI genomic region	0 (Continue Evaluation)	0
	2C. Partial overlap with the 5’ end of an established HI gene (3’ end of the gene not involved)…	See categories below
	2C-1. …and coding sequence is involved	0.90 (Range: 0.45 to 1.00)	1.00
	2C-2. …and only the 5’ UTR is involved	0 (Range: 0 to 0.45)	0.45
	2D. Partial overlap with the 3’ end of an established HI gene (5’ end of the gene not involved) …	See categories below
	2D-1 …and only the 3’ untranslated region is involved.	0 (Continue evaluation)	0
	2D-2. …and only the last exon is involved. Other established pathogenic variants have been reported in this exon.	0.90 (Range: 0.45 to 0.90)	0.90
	2D-3. …and only the last exon is involved. No other established pathogenic variants have been reported in this exon.	0.30 (Range: 0 to 0.45)	0.45
	2D-4. …and it includes other exons in addition to the last exon. Nonsense-mediated decay is expected to occur.	0.90 (Range: 0.45 to 1.00)	1.00
	2E. Both breakpoints are within the same gene (intragenic CNV; gene-level sequence variant)	See ClinGen SVI working group PVS1 specifications PVS1= 0.90 (Range: 0.45 to 0.90) PVS1_Strong= 0.45 (Range: 0.30 to 0.90) PVS1_Moderate or PM4 (in-frame indels) = 0.30 (Range: 0.15 to 0.45) PVS1_Supporting = 0.15 (Range: 0 to 0.30) N/A = No points, but continue evaluation	See categories at left
Overlap with ESTABLISHED benign genes or genomic regions	2F. Completely contained within an established benign CNV region	−1	−1
	2G. Overlaps an established benign CNV, but includes additional genomic material	0 (Continue evaluation)	0
Haploinsufficiency Predictors	2H. Two or more HI predictors suggest that AT LEAST ONE gene in the interval is haploinsufficient (HI)	0.15	0.15
Section 3: Evaluation of Gene Number
Number of protein-coding RefSeq genes wholly or partially included in the copy number loss	3A. 0-24 genes	0	0
	3B. 25-34 genes	0.45	0.45
	3C. 35+ genes	0.90	0.90
Section 4: Detailed Evaluation of Genomic Content Using Cases from Published Literature, Public Databases, and/or Internal Lab Data (Skip to Section 5 if either your CNV overlapped with an established HI gene/region in Section 2, OR there have been no reports associating either the CNV or any genes within the CNV with human phenotypes caused by loss of function (LOF) or copy number loss)
Individual case evidence – de novo occurrences	Reported proband (from literature, public databases, or internal lab data) has either: A complete deletion of or a LOF variant within gene encompassed by the observed copy number loss OR an overlapping copy number loss similar in genomic content to the observed copy number loss AND…	See categories below
	4A. …the reported phenotype is highly specific and relatively unique to the gene or genomic region	Confirmed de novo: 0.45 points each Assumed de novo: 0.30 points each (Range: 0.15 to 0.45)	0.90 (total)
	4B. …the reported phenotype is consistent with the gene/genomic region, is highly specific, but not necessarily unique to the gene/genomic region	Confirmed de novo: 0.30 points each Assumed de novo: 0.15 point each (Range: 0 to 0.45)
	4C. …the reported phenotype is consistent with the gene/genomic region, but not highly specific and/or with high genetic heterogeneity	Confirmed de novo: 0.15 point each Assumed de novo: 0.10 point each (Range: 0 to 0.30)
Individual case evidence – inconsistent phenotype	4D.…the reported phenotype is NOT consistent with what is expected for the gene/genomic region or not consistent in general	0 points each (Range: 0 to −0.30)	−0.30 (total)
Individual case evidence – unknown inheritance	4E. Reported proband has a highly specific phenotype consistent with the gene/genomic region, but the inheritance of the variant is unknown.	0.10 points each (Range: 0 to 0.15)	0.30 (total)
Individual case evidence – segregation among similarly affected family members	4F. 3-4 observed segregations	0.15	0.45
	4G. 5-6 observed segregations	0.30
	4H. 7 or more observed segregations	0.45
Individual case evidence - Non-Segregations	4I. Variant is NOT found in another individual in the proband’s family AFFECTED with a consistent, specific, well-defined phenotype (no known phenocopies)	−0.45 points per family (Range: 0 to −0.45)	−0.90 (Total)
	4J. Variant IS found in another individual in the proband’s family UNAFFECTED with the specific, well-defined phenotype observed in the proband	−0.30 points per family (Range: 0 to −0.30)	−0.90 (Total)
	4K. Variant IS found in another individual in the proband’s family UNAFFECTED with the non-specific phenotype observed in the proband	−0.15 points per family (Range: 0 to −0.15)	−0.30 (Total)
Case-control and population evidence	4L. Statistically significant increase amongst observations in cases (with a consistent, specific, well-defined phenotype) compared to controls	0.45 per study (Range: 0 to 0.45 per study)	0.45 (total)
	4M. Statistically significant increase amongst observations in cases (without a consistent, non-specific phenotype OR unknown phenotype) compared to controls	0.30 per study (Range:0 to 0.30 per study)	0.45 (total)
	4N. No statistically significant difference between observations in cases and controls	−0.90 (per study) (Range:0 to −0.90 per study)	−0.90 (total)
	4O. Overlap with common population variation	−1 (Range:0 to −1)	−1
Section 5: Evaluation of Inheritance Pattern/Family History for Patient Being Studied
Observed copy number loss is DE NOVO	5A. Use appropriate category from de novo scoring section in Section 4.	Use de novo scoring categories from Section 4 (4A-4D) to determine score.	0.45
Observed copy number loss is INHERITED	5B. Patient with specific, well-defined phenotype and no family history. CNV is inherited from an apparently unaffected parent.	−0.30 (Range: 0 to −0.45)	−0.45
	5C. Patient with non-specific phenotype and no family history. CNV is inherited from an apparently unaffected parent.	−0.15 (Range: 0 to −0.30)	−0.30
	5D. CNV segregates with a consistent phenotype observed in the patient’s family.	Use segregation scoring categories from Section 4 (4F-4H) to determine score.	0.45
Observed copy number loss – NON-SEGREGATIONS	5E. Use appropriate category from non-segregation section in Section 4.	Use non-segregation scoring categories from Section 4 (4I-4K) to determine score.	−0.45
Other	5F. Inheritance information is unavailable or uninformative.	0	0
	5G. Inheritance information is unavailable or uninformative. The patient phenotype is non-specific, but is consistent with what has been described in similar cases.	0.10 (Range: 0 to 0.15)	0.15
	5H. Inheritance information is unavailable or uninformative. The patient phenotype is highly specific and consistent with what has been described in similar cases.	0.30 (Range: 0 to 0.30)	0.30

Note: Only those CNVs otherwise meeting the reporting thresholds determined by your laboratory should be evaluated using this metric.

See Supplemental Material 1 for a detailed description of each evidence category