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Please note this is a beta version of the ClinGen Evidence Repository. This resource is intended to provide access to variant level evidence used and applied by ClinGen Variant Curation Expert Panels in the classification of variants. In this beta version, the evidence is limited to curation notes and referenced literature (PMIDs).

For general information about ClinGen Expert Panels and Variant Curation please visit: Clinical Domain Working Groups. For specific inquiries regarding a variant classification or evidence curation (e.g. population database queried, segregation counts or other evidence used) or to submit general comments about the evidence repo, please email us.

The resource is undergoing updates and tesing. Should you encounter any issues regarding the data displayed, lack of functionality or other problems, please let us know so we can rectify these accordingly. Your help in this regard is greatly appreciated.

Hearing Loss ACMG Specifications v1 2018

Benign
Pathogenic
Stand Alone
Strong
Supporting
Supporting
Moderate
Strong
Very Strong
Population Data

MAF of ≥0.005 (0.5%) for autosomal recessive; MAF of ≥0.001 (0.1%) for autosomal dominant BA1

MAF of ≥0.003 (0.3%) for autosomal recessive; MAF of ≥0.0002 (0.02%) for autosomal dominant. Likely benign, provided there is no conflicting evidence. BS1

Observation of variant (biallelic with known pathogenic variant for recessive) in controls inconsistent with disease penetrance. BS2

MAF of ≥0.0007 (0.07%) for autosomal recessive. No BS1_Supporting criteria for autosomal dominant. BS1-Supporting

Low MAF in population databases (<0.0007 [0.07%] for autosomal recessive), No PM2_Supporting for autosomal dominant genes PM2-Supporting

Autosomal dominant: ≥2 probands with variant, and variant meets PM2 PS4-Supporting

Absent/rare in population databases (absent or ≤0.00007 [0.007%] for autosomal recessive, ≤0.00002 [0.002%] for autosomal dominant) PM2

Autosomal dominant: ≥6 probands with variant, and variant meets PM2 PS4-Moderate

Fisher Exact or Chi-squared analysis shows statistical increase in cases over controls, or for Autosomal dominant: ≥15 probands with variant, and variant meets PM2 PS4

Computational And Predictive Data

In-frame indels in repeat region without known function BP3

Computational evidence suggests no impact; REVEL score ≤0.15 or no impact to splicing in MaxEntScan. BP4

Silent variant with no predicted impact to splicing BP7

REVEL score ≥0.7, or predicted impact to splicing using MaxEntScan PP3

See PVS1 flowchart for PVS1_Supporting variants in gene where LOF is a known mechanism of disease. (PMID: 30192042) PVS1-Supporting

See PVS1 flowchart for PVS1_Moderate variants in gene where LOF is a known mechanism of disease. (PMID: 30192042) PVS1-Moderate

Protein length change due to an in-frame deletion or insertion that are not located in repetitive regions PM4

Missense change at same codon as another pathogenic missense variant PM5

Missense change at same codon as two different pathogenic missense variants PM5-Strong

Same amino acid change as an established pathogenic variant or splice variants at same nucleotide and with similar impact prediction as the previously reported pathogenic variant PS1

See PVS1 flow chart for PVS1_Strong variants in gene where LOF is a known mechanism of disease. (PMID: 30192042) PVS1-Strong

Null variant in a gene with established LOF as a disease mechanism; see PVS1_Strong, PVS1_Moderate, and PVS1_Supporting for reduced evidence applications. (PMID: 30192042) PVS1

Functional Data

Functional study shows no deleterious effect (predefined list) BS3-Supporting

Functional studies with limited validation show a deleterious effect PS3-Supporting

Validated functional studies show a deleterious effect (predefined list) PS3-Moderate

Mutational hot spot or well-studied functional domain without benign variation (KCNQ4 pore-forming region; Gly residues in Gly-X-Y motifs of collagen genes such as COL4A3/4/5) PM1

Knock-in mouse model demonstrates the phenotype PS3

Segregation Data

Nonsegregation with disease BS4

Segregation in one affected relative for recessive and two affected relatives for dominant PP1

Segregation in two affected relatives for recessive and 4 affected relatives for dominant PP1-Moderate

Segregation in three affected relatives for recessive and five affected relatives for dominant PP1-Strong

De novo Data

0.5 points per tables [6](https://onlinelibrary.wiley.com/doi/full/10.1002/humu.23630#humu23630-tbl-0006) and [7] (https://onlinelibrary.wiley.com/doi/full/10.1002/humu.23630#humu23630-tbl-0007): Example: 1 assumed de novo occurrence (phenotype/gene not specific) PS2-Supporting

See PS2 above PM6

1 point per tables [6](https://onlinelibrary.wiley.com/doi/full/10.1002/humu.23630#humu23630-tbl-0006) and [7] (https://onlinelibrary.wiley.com/doi/full/10.1002/humu.23630#humu23630-tbl-0007):
* Examples: 1 proven de novo occurrence (phenotype consistent but not specific to gene); OR 1 assumed de novo occurrence; OR 2 assumed de novo occurrences (phenotype/gene not specific) PS2-Moderate

2 points per tables [6](https://onlinelibrary.wiley.com/doi/full/10.1002/humu.23630#humu23630-tbl-0006) and [7] (https://onlinelibrary.wiley.com/doi/full/10.1002/humu.23630#humu23630-tbl-0007)
* Examples: 1 proven de novo occurrence; OR 2 assumed de novo occurrences PS2

4 points per tables [6](https://onlinelibrary.wiley.com/doi/full/10.1002/humu.23630#humu23630-tbl-0006) and [7] (https://onlinelibrary.wiley.com/doi/full/10.1002/humu.23630#humu23630-tbl-0007):
* Examples: 2 proven de novo occurrences; OR 1 proven + 1 assumed de novo occurrences; OR 4 assumed de novo occurrences PS2-Very Strong

Allelic Data

Observed in trans with a dominant variant/observed in cis with a pathogenic variant (use with caution) BP2

0.5 points awarded from Tables [8](https://onlinelibrary.wiley.com/doi/full/10.1002/humu.23630#humu23630-tbl-0008) and [9] (https://onlinelibrary.wiley.com/doi/full/10.1002/humu.23630#humu23630-tbl-0009)
* Examples: Two variants that meet PM2_Supporting detected in trans or a homozygous variant meeting PM2_Supporting PM3-Supporting

1 point awarded from Tables [8](https://onlinelibrary.wiley.com/doi/full/10.1002/humu.23630#humu23630-tbl-0008) and [9] (https://onlinelibrary.wiley.com/doi/full/10.1002/humu.23630#humu23630-tbl-0009)
* Example: Detected in trans with a pathogenic variant (recessive) PM3

2 points awarded from Tables [8](https://onlinelibrary.wiley.com/doi/full/10.1002/humu.23630#humu23630-tbl-0008) and [9] (https://onlinelibrary.wiley.com/doi/full/10.1002/humu.23630#humu23630-tbl-0009)
* Example: Detected in trans in 2 probands with a pathogenic variant (recessive) PM3-Strong

4 points awarded from Tables [8](https://onlinelibrary.wiley.com/doi/full/10.1002/humu.23630#humu23630-tbl-0008) and [9] (https://onlinelibrary.wiley.com/doi/full/10.1002/humu.23630#humu23630-tbl-0009)
* Example: Detected in trans in ≥4 probands with a pathogenic variant (recessive) PM3-Very Strong

Other Data

Variant in an autosomal dominant gene found in a patient with an alternate explanation BP5

Patient's phenotype highly specific for gene or fully sequenced gene set (see specifications in Table [10](https://onlinelibrary.wiley.com/doi/full/10.1002/humu.23630#humu23630-tbl-0010)) PP4

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