×

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.

LSD VCEP ACMG/AMP Specifications

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

Common in population databases.
•Highest minor allele frequency >0.01 (>1%) in any continental population in gnomAD with >2000 alleles. BA1

Allele frequency greater than expected for disease.
•Highest minor allele frequency >0.005 (>0.5%) in any continental population in gnomAD with >2000 alleles. BS1

Low frequency in population databases.
•Minor allele frequency <0.1% (0.001) in all continental populations with >2000 alleles in gnomAD. PM2

Computational And Predictive Data

Multiple lines of computational evidence suggest no impact on gene or gene product.
•REVEL score <0.5 for missense variants.
•In frame deletion or insertion predicted benign by PROVEAN and MutationTaster.
•No predicted impact on splicing by Human Splicing Finder and MaxEntScan. BP4

A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved BP7

Missense change at an amino acid residue where a different missense change determined to be “likely pathogenic” has been seen before. PM5-Supporting

Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
•In frame deletion/insertions of one amino acid. PM4-Supporting

Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
•REVEL score >0.75 for missense variants.
•In frame deletion or insertion predicted deleterious by PROVEAN and MutationTaster.
•Predicted impact on splicing by Human Splicing Finder and MaxEntScan. PP3

Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
•In frame deletion/insertions of two or more amino acids but less than one exon. PM4

Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. PM5

Null variant in a gene where loss of function is a known mechanism of disease.
•Premature termination codon in the 3' end of GAA, not predicted to be detected by nonsense-mediated decay.
•Predicted exon-skipping due to canonical splice variant or exon deletion resulting in an in frame deletion of <10% of the gene product. PVS1-Moderate

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. PS1

Null variant in a gene where loss of function is a known mechanism of disease.
•In frame loss of an exon which is part of the catalytic barrel and contains pathogenic/likely pathogenic non-truncating variants.
•Initiator codon variant. PVS1-Strong

Null variant in a gene where loss of function is a known mechanism of disease or in frame loss of an exon that contains residues involved in the active site of GAA. PVS1

Functional Data

Well-established in vitro or in vivo functional studies show no damaging effect on protein function.
•>60% normal GAA activity when the variant is expressed in a heterologous cell type. BS3

Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
•40-60% normal GAA activity, or 30-60% activity AND evidence of normal GAA synthesis/processing, when the variant is expressed in a heterologous cell type. BS3-Supporting

Well-established in vitro or in vivo functional studies supportive of a damaging effect.
•10-30% normal GAA activity when the variant is expressed in a heterologous cell type.
•RT-PCR evidence of mis-splicing for non-canonical intronic variants with the additional presence of normal splice products.
•CRIM-negative status in patient cells for a non-canonical splice variant. PS3-Supporting

Well-established in vitro or in vivo functional studies supportive of a damaging effect.
•10-30% normal GAA activity AND evidence of abnormal GAA synthesis/processing when the variant is expressed in a heterologous cell type.
•RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products. PS3-Moderate

Well-established in vitro or in vivo functional studies supportive of a damaging effect.
•<10% normal GAA activity when the variant is expressed in a heterologous cell type.
•RT-PCR evidence of mis-splicing for non-canonical intronic variants with no evidence of normal splice products PS3

Allelic Data

Observed in cis with a pathogenic variant. BP2

Detected in trans with a pathogenic variant. Consult specifications for assigning strength of evidence for PM3. PM3-Supporting

Detected in trans with a pathogenic variant. Consult specifications for assigning strength of evidence for PM3 PM3

Detected in trans with a pathogenic variant. Consult guidelines for assigning strength of evidence for PM3. PM3-Strong

Detected in trans with a pathogenic variant. Consult guidelines for assigning strength of evidence for PM3. PM3-Very Strong

Other Data

Phenotype specific for disease with single genetic etiology.
•<10% GAA activity in lymphocytes, leukocytes, or muscle or <30% activity in cultured fibroblast; or GAA activity in affected range in a clinically validated assay; and no report of pseudodeficiency variant(s). PP4

Phenotype specific for disease with single genetic etiology.
•<10% GAA activity in lymphocytes, leukocytes, or muscle or <30% activity in cultured fibroblast; or GAA activity in affected range in a clinically validated assay AND absence of pseudodeficiency variant(s) confirmed by sequence analysis. PP4-Moderate

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.