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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.

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ACMG variant classification Familial Hypercholesterolemia

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

Variant has a PopMax FAF >0.005 (0.5%) in gnomAD. LDLR-specific population data frequency thresholds.
•Filtering allele frequency - ≥0.005 (0.5%) BA1 metrics were equal to 0.4%; however, we conservatively increased the BA1 threshold to 0.5%. * Prevalence - 1/250; * Penetrance - 50% * Allelic heterogeneity - 1.0 * Genetic heterogeneity - 1.0 BA1

Variant is identified in ≥3 heterozygous or ≥1 homozygous wellphenotyped normolipidemic adults (unrelated). BS2

Variant has a PopMax FAF >0.002 (0.2%) in gnomAD. LDLR-specific population data frequency thresholds.
•Filtering allele frequency - ≥0.002 (0.2%) * Prevalence - 1/250; * Penetrance - 95% * Allelic heterogeneity - 1.0 * Genetic heterogeneity - 0.9 BS1

Variant is found in 2-5 unrelated FH cases (FH diagnosis made by any validated clinical criteria). Caveat: variant must also meet PM2 (i.e. FAF <0.02%). PS4-Supporting

Variant is found in 6-9 unrelated FH cases (FH diagnosis made by any validated clinical criteria). Caveat: variant must also meet PM2 (i.e. FAF <0.02%). PS4-Moderate

Variant has a PopMax FAF <0.0002 (0.02%) in gnomAD. LDLR-specific population data frequency thresholds.
•Filtering allele frequency - ≤0.0002 (0.02%) * Prevalence - 1/250; * Penetrance - 95% * Allelic heterogeneity - 0.1 * Genetic heterogeneity - 0.9 PM2

Variant is found in ≥10 unrelated FH cases (FH diagnosis met by any validated clinical criteria). Caveat: variant must also meet PM2 (i.e. FAF <0.02%). PS4

Computational And Predictive Data

Variant is synonymous. Caveat: variant must also meet BP4 (i.e. no predicted impact on splicing). BP7

Computational evidence supports no impact on gene or gene product. See FH VCEP suggestions for missense/splicing predictors in main text BP4

In-frame deletions/insertions in a repetitive region without a known function BP3

Missense variant in gene where only LOF causes disease BP1

Computational evidence supports a deleterious effect on the gene or gene product. See FH VCEP suggestions for missense/splicing predictors in main text. PP3

Missense variant at the same codon as a variant classified pathogenic (with 3-star status in ClinVar), and leads to a different amino acid change. PM5

In-frame deletion/insertions smaller than one whole exon, or inframe whole-exon duplications not considered in any PVS1 criteria. Caveat: variant must also meet PM2 (i.e. FAF <0.02%). PM4

See main text for specific variant types - PVS1 downgraded in strength to Moderate PVS1-Moderate

Missense variant at a codon with ≥2 missense variants classified pathogenic (with 3-star status in ClinVar), and leads to a different amino acid change. PM5-Strong

See main text for specific variant types PVS1-Strong

Missense variant at the same codon as a variant classified pathogenic (with 3-star status in ClinVar), and leads to the same amino acid change.Caveat: there is no in silico predicted splicing impact for either variant. PS1

See main text for specific variant types - null variant in a gene where LOF is a known mechanism of disease PVS1

Functional Data

Variant meets Level 1 benign functional study criteria.
•Study of the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding, and LDL internalization) performed in heterologous cells (with no endogenous LDLR) transfected with mutant plasmid. Assay result of <90% of wild-type activity in expression/biosynthesis, binding AND internalization. Note: studies of only part of the LDLR cycle are not eligible for BS3 or BS3_Supporting. BS3

Variant meets Level 3 benign functional study criteria.
•Study of whole LDLR cycle in ** true homozygous patient cells, with assay result of >90% of wild-type activity in biosynthesis, binding AND internalization; or in ** heterozygous patient cells with assay result of >95% of wild-type activity in biosynthesis, binding AND internalization. ** Luciferase studies with transcription levels of >90% when compared to wildtype (applicable to 5’UTR/promoter variants). ** RNA studies, using RNA extracted from heterozygous or homozygous patient cells, with a) aberrant transcripts quantification, where aberrant transcript is <10% of total transcript OR b) without transcript quantification where no aberrant transcript is confirmed by sequencing. ** Minigene splicing assay where only wild-type transcript is present and confirmed by sequencing. ** High-throughput assays as defined above; only applicable when assay can indicate the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding AND internalization) is unaffected. BS3-Supporting

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PP2

Variant meets Level 3 pathogenic functional study criteria.
•Study of LDLR cycle (part or whole) in heterozygous patient cells, with assay results of <85% of wild-type activity in either LDLR expression/biosynthesis, LDL binding OR internalization. * Luciferase studies with transcription levels of <50% compared to wild-type (applicable to 5’UTR/promoter variants). * Minigene splicing assays with <10% wild-type transcript present where an aberrant transcript from the candidate variant is confirmed by sequencing. * High-throughput assays, which include alternative microscopy assays (Thormaehlen et al., 2015), Multiplex Assays of Variant Effect (MAVE) (Weile & Roth, 2018) and deep mutational scanning assays, can be considered here, only if assay has been validated with a minimum of 4 pathogenic and 4 benign variant controls in LDLR. *Note: % activity thresholds will be defined by the FH VCEP as more data becomes available. Roth, 2018) and deep mutational scanning assays, can be considered here, only if assay has been validated with a minimum of 4 pathogenic and 4 benign variant controls in LDLR. *Note: % activity thresholds will be defined by the FH VCEP as more data becomes available. * RNA studies, using RNA extracted from heterozygous or homozygous patient cells, with aberrant transcript confirmed by sequencing (but without transcript quantification). PS3-Supporting

Variant meets Level 2 pathogenic functional study criteria.
•Study of ** only part of the LDLR cycle following Level 1 methodology, ** whole or part of LDLR cycle in true homozygous patient cells. A variant with assay results of <70% of wild type activity in either LDLR expression/biosynthesis, LDL binding OR internalization.* RNA studies, using RNA extracted from heterozygous or homozygous patient cells, where aberrant transcript is confirmed by sequencing and is quantified as >25% of total transcript from heterozygous cells or 50% of total transcript from homozygous cells. * Variants with two or more Level 3 functional studies (must be different assays); or any Level 3 functional study #1-4 performed by two or more independent labs with concordant results. PS3-Moderate

Missense variant is located in exon 4, or is a missense change in one of 60 highly conserved cysteine residues. Caveat: variant must also meet PM2 (i.e. FAF <0.02%) PM1

Variant meets Level 1 pathogenic functional study criteria. Study of the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding,and LDL internalization) performed in heterologous cells (with no endogenous LDLR) transfected with mutant plasmid. Assay result of <70% of wild-type activity in either expression/biosynthesis, binding OR internalization. PS3

Segregation Data

Lack of segregation in ≥2 index case families (unrelated), when data is available for ≥2 informative meioses in each family. Caveat: must be ≥1 affected relative (LDL-C >75th percentile) who does not carry the variant. BS4

Variant segregates with phenotype in 2-3 informative meioses in ≥1 family. Must include ≥1 affected relative (LDL-C >75th percentile) with the variant. PP1

Variant segregates with phenotype in 4-5 informative meioses in ≥1 family. Must include ≥2 affected relatives (LDL-C >75th percentile) with the variant. PP1-Moderate

Variant segregates with phenotype in ≥6 informative meioses in ≥1 family. Must include ≥2 affected relatives (LDL-C >75th percentile) with the variant. PP1-Strong

De novo Data

Variant is de novo in a patient with the disease and no family history. Follow SVI guidance for de novo occurrences:https://clinicalgenome.org/working-groups/sequence-variantinterpretation// PM6

Variant is de novo in a patient with the disease and no family history. Follow SVI guidance for de novo occurrences :https://clinicalgenome.org/working-groups/sequence-variantinterpretation// PS2

Allelic Data

If a FH patient with a heterozygous phenotype carries a proven pathogenic variant in LDLR, APOB or PCSK9, BP2 is applicable to any additional LDLR variants. BP2

This criterion can be used for a candidate LDLR variant observed in an individual with a homozygous FH phenotype when there is only one other pathogenic variant in LDLR (must be in trans), APOB or PCSK9. Caveat: variant must also meet PM2 (i.e. FAF <0.02%). PM3

Other Database

Reputable source recently reports variant as benign but the evidence is not available to the laboratory to perform an independent evaluation BP6

Reputable source recently reports variant as pathogenic but the evidence is not available to the laboratory to perform an independent evaluation PP5

Other Data

Variant found in a case with an alternate molecular basis for disease BP5

Any LDLR variant identified in an FH patient [diagnosis based on any validated clinical criteria, ex. Dutch Lipid Clinic Network (≥6), Simon Broome (possible/definite), MEDPED], after alternative causes of high cholesterol are excluded. PP4

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