Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000527.5(LDLR):c.2000G>A (p.Cys667Tyr)

CA023621

3689 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 218276d3-2d8e-4ff6-8f45-a17666d02565

Approved on: 2021-06-18

Published on: 2021-06-24

HGVS expressions

NM_000527.5:c.2000G>A

NM_000527.5(LDLR):c.2000G>A (p.Cys667Tyr)

ENST00000558518.6:c.2000G>A

ENST00000252444.9:n.2254G>A

ENST00000455727.6:c.1496G>A

ENST00000535915.5:c.1877G>A

ENST00000545707.5:c.1606+149G>A

ENST00000557933.5:c.2000G>A

ENST00000558013.5:c.2000G>A

ENST00000558518.5:c.2000G>A

ENST00000559340.1:n.581G>A

NM_000527.4:c.2000G>A

NM_001195798.1:c.2000G>A

NM_001195799.1:c.1877G>A

NM_001195800.1:c.1496G>A

NM_001195803.1:c.1606+149G>A

NM_001195798.2:c.2000G>A

NM_001195799.2:c.1877G>A

NM_001195800.2:c.1496G>A

NM_001195803.2:c.1606+149G>A

NC_000019.10:g.11120382G>A

CM000681.2:g.11120382G>A

NC_000019.9:g.11231058G>A

CM000681.1:g.11231058G>A

NC_000019.8:g.11092058G>A

NG_009060.1:g.36002G>A

Likely Pathogenic

PS3_Moderate PP4 PP3 PM1 PM2 PS4_Supporting

PP1 PP2 PM3 PM4 PM5 PM6 PS2 PS1 BA1 PVS1 BP5 BP7 BP2 BP3 BP4 BP1 BS2 BS4 BS3 BS1

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

NM_000527.5(LDLR):c.2000G>A (p.Cys667Tyr) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM1, PM2, PS3_Moderate, PP3, PP4 and PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM1 - Variant meets PM2 and is one of listed Cysteine. PM2 - PopMax MAF = 0.000008794 (0.0009%) in European non-Finnish exomes (gnomAD v2.1.1). PS3_moderate - PMID:2318961 - Level 2 assay - study on hmz patient's fibroblasts, after 2 hours pulse-chase, only 20% of receptors were processed to the mature form. Also here PMID: 14993243 and here PMID: 10906332 is shown that this mutant is retained on ER. In last two papers not whole LDLR cycle was studied. PP3 - REVEL: 0,986. PP4 - Variant meets PM2. Variant found in 5 unrelated index cases fulfilling validated clinical criteria for FH. PS4_supporting - Variant meets PM2. Variant identified in 5 unrelated index cases (1 case from Color laboratory with Simon-Broome criteria; 1 case from Ambry Genetics with Simon-Broome criteria; 1 case from GeneDx Inc. with Simon-Broome criteria; 2 cases from University of British Columbia with DLCN score 16 and 10, respectively).

PS3_Moderate

PMID:2318961 - Level 2 assay - study on hmz patient's fibroblasts, after 2 hours pulse-chase, only 20% of receptors were processed to the mature form. Also here PMID: 14993243 and here PMID: 10906332 is shown (CHO cells, Chang cells respectively) that this mutant is retained on ER. In last two papers not whole LDLR cycle was studied.

PP4

Variant meets PM2. Variant found in 5 unrelated index cases fulfilling validated clinical criteria for FH.

PP3

REVEL: 0,986. Score is above 0,75.

PM1

Variant meets PM2 and is one of listed Cysteine. S-S bond with Cys681.

PM2

PopMax MAF = 0.000008794 (0.0008794%) in European non-Finnish exomes (gnomAD v2.1.1). MAF is below 0.02%.

PS4_Supporting

Variant meets PM2. Variant identified in 5 unrelated index cases (1 case from Color laboratory with Simon-Broome criteria; 1 case from Ambry Genetics with Simon-Broome criteria; 1 case from GeneDx Inc. with Simon-Broome criteria; 2 cases from University of British Columbia with DLCN score 16 and 10, respectively).

PP1

No family members tested.

PP2

Not applicable.

PM3

Not identified in individuals with other variants.

PM4

Missense variant. Not applicable.

PM5

Variant meets PM1, so not applicable

PM6

No de novo cases were identified.

PS2

No de novo cases were identified.

PS1

Variant meets PM1, so not applicable

BA1

no FAF, just total MAF = 0.000003978 (0.0004%) in European non-Finnish exomes (gnomAD v2.1.1). MAF is not above 0.5%

PVS1

Missense variant. Not applicable.

BP5

Not applicable.

BP7

Missense variant. Not applicable.

BP2

Not identified in individuals with other variants.

BP3

Not applicable.

BP4

REVEL: 0,986. Score is not below 0,50.

BP1

Not applicable.

BS2

No unaffected individuals identified with the variant.

BS4

No family members tested.

BS3

PMID:2318961 - Level 2 assay - only 20% of receptors were processed to the mature form. Also here PMID: 14993243 and here PMID: 10906332 is shown that this mutant is retained on ER. BS3 is not met.

BS1

no FAF, just total MAF = 0.000003978 (0.0004%) in European non-Finnish exomes (gnomAD v2.1.1). MAF is not above 0.2%

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