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.259T>G (p.Trp87Gly)

CA023683

3685 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: fe3c7d4d-c876-42cf-b2ec-d228ee2c5d24

HGVS expressions

NM_000527.5:c.259T>G

NM_000527.5(LDLR):c.259T>G (p.Trp87Gly)

ENST00000558518.6:c.259T>G

ENST00000252444.9:n.513T>G

ENST00000455727.6:c.259T>G

ENST00000535915.5:c.190+2387T>G

ENST00000545707.5:c.259T>G

ENST00000557933.5:c.259T>G

ENST00000557958.1:n.345T>G

ENST00000558013.5:c.259T>G

ENST00000558518.5:c.259T>G

NM_000527.4:c.259T>G

NM_001195798.1:c.259T>G

NM_001195799.1:c.190+2387T>G

NM_001195800.1:c.259T>G

NM_001195803.1:c.259T>G

NM_001195798.2:c.259T>G

NM_001195799.2:c.190+2387T>G

NM_001195800.2:c.259T>G

NM_001195803.2:c.259T>G

NC_000019.10:g.11102732T>G

CM000681.2:g.11102732T>G

NC_000019.9:g.11213408T>G

CM000681.1:g.11213408T>G

NC_000019.8:g.11074408T>G

NG_009060.1:g.18352T>G

Pathogenic

PS3 PS4 PP1_Moderate PP4 PP3 PM2

PS2 PS1 BP2 BP3 BP4 BP1 BP5 BP7 BA1 PP2 PM3 PM4 PM1 PM5 PM6 PVS1 BS2 BS1 BS4 BS3

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.259T>G (p.Trp87Gly) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS3, PS4, PP1_Moderate, PM2, PP3 and PP4) 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: PS3 - Level 1/2 assays: PMID 31578082: Hmz patients' lymphocytes, FACS assays and Heterologous cells (CHO), WB, FACS and CLSM assays - results - lymphocytes: normal cell surface LDLR, 40% LDL-LDLR binding, 35% uptake; CHO: normal (100%) LDLR expression, 20% LDL-LDLR binding, 35% uptake ---- binding and uptake are below 70% of wild-type, so PS3 is Met. PS4 - Variant meets PM2. Variant identified in at least 13 unrelated index cases with Dutch Lipid Clinic score equal or above 6 from different labs. PP1_moderate - variant segregates with FH phenotype in 5 informative meiosis in 2 families from different labs. PM2 - PopMax MAF = 0.00005418 (0.0054%) in european non-finnish exomes (gnomAD v2.1.1). PP3 - REVEL = 0.892. PP4 - Variant meets PM2. Identified in 13 unrelated index cases with Dutch Lipid Clinic score equal or above 6 from different labs.

PS3

Level 1/2 assays: PMID 31578082: Hmz patients' lymphocytes, FACS assays and Heterologous cells (CHO), WB, FACS and CLSM assays - results - lymphocytes: normal cell surface LDLR, 40% LDL-LDLR binding, 35% uptake; CHO: normal (100%) LDLR expression, 20% LDL-LDLR binding, 35% uptake ---- binding and uptake are below 70% of wild-type, so PS3 is Met (PS3_moderate would also be Met, but PS3 is already Met) / Level 3 assays: PMID 10735631: Htz patients' stimulated T-lymphocytes, FACS - results - 79% LDLR cell surface, 68% LDL-LDLR binding and 88% uptake, they suggests that the W66G mutation disrupts the recycling of LDL receptors (class V) ---- cell surface and binding are below 85% of wild-type, so PS3_supporting would be Met, but PS3 is already Met / Level 2 assays: PMID 1301956: Hmz patients' fibroblasts, 125I-LDL assays - results - 25-100% LDLR activity (25 to 55% of normal in subject 1, 30 to 50% in subject 2, and 65 to 100% in subject 3) ---- too much variability, do not use in either BS3 or PS3 / Level 2 assays: PMID 7584986: Hmz patients' fibroblasts, 125I-LDL assays - results - 20-90% LDLR activity ---- too much variability, do not use in either BS3 or PS3

PS4

Variant meets PM2. Variant identified in at least 13 unrelated index cases with Dutch Lipid Clinic score equal or above 6 from different labs (Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) and University of British Columbia --- PS4 is Met

PP1_Moderate

variant segregates with FH phenotype in 5 informative meiosis in 2 families from different labs (Center of molecular biology and gene therapy and University of British Columbia): 5 affected family members have the variant. --- PP1_Moderate is Met

PP4

Variant meets PM2. Identified in 13 unrelated index cases with Dutch Lipid Clinic score equal or above 6 from different labs (University of British Columbia (UBC, Canada) and Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA)). ---- PP4 is Met

PP3

REVEL = 0.892. It is above 0.75, so PP3 is Met

PM2

PopMax MAF = 0.00005418 (0.0054%) in european non-finnish exomes (gnomAD v2.1.1).

PS2

no de novo cases were identified, so PS2 is Not Met

PS1

No other reported missense variant that leads to the same amino acid change, PS1 is Not Met

BP2

1 index case from University of British Columbia (#5) also has NM_000527.5(LDLR):c.718G>A (p.Glu240Lys) (ClinVar ID 200920) variant but phenotype does not rule out or confirm Homozygous FH. --- BP2 is not met

BP3

Not applicable

BP4

REVEL = 0.892. It is not below 0.15 and PP3 is Met, so BP4 is Not Met

BP1

Not applicable

BP5

Not applicable

BP7

Missense variant, so BP7 is not applicable

BA1

FAF = 0.00002853 (0.003%) in european non-finnish exomes (gnomAD v2.1.1). FAF is not above 0.5%, so BA1 is Not Met

PP2

Not applicable

PM3

PM4

Missense variant, not applicable

PM1

Missense at codon 87. PM2 is Met, but it is not exon 4 or any of the 60 Cys residues listed, so PM1 is Not Met

PM5

One more missense variant in the same codon: (1)NM_000527.4(LDLR):c.259T>C (p.Trp87Arg) (ClinVar ID 440552) - VUS by these guidelines. so PM5 is Not Met

PM6

no de novo cases were identified, so PM6 is Not Met

PVS1

Missense variant not in initiation codon, PVS1 Not Met

BS2

no unaffected individuals identified with the variant, so BS2 is Not Met

BS1

FAF = 0.00002853 (0.003%) in european non-finnish exomes (gnomAD v2.1.1). FAF is not above 0.2%, so BS1 is Not Met.

BS4

no non-segregations were identified, so BS4 is Not Met

BS3

Level 1/3(benign) assays: PMID 31578082: Hmz patients' lymphocytes, FACS assays and Heterologous cells (CHO), WB, FACS and CLSM assays - results - lymphocytes: normal cell surface LDLR, 40% LDL-LDLR binding, 35% uptake; CHO: normal (100%) LDLR expression, 20% LDL-LDLR binding, 35% uptake ---- whole cycle is not above 90% of wild-type, so BS3/BS3_supporting are Not Met / Level 3 assays: PMID 10735631: Htz patients' stimulated T-lymphocytes, FACS - results - 79% LDLR cell surface, 68% LDL-LDLR binding and 88% uptake, they suggests that the W66G mutation disrupts the recycling of LDL receptors (class V) ---- whole cycle is not above 95% of wild-type, so BS3_supporting is Not Met / Level 3(benign) assays: PMID 1301956: Hmz patients' fibroblasts, 125I-LDL assays - results - 25-100% LDLR activity (25 to 55% of normal in subject 1, 30 to 50% in subject 2, and 65 to 100% in subject 3) ---- too much variability, do not use in either BS3 or PS3 / Level 3(benign) assays: PMID 7584986: Hmz patients' fibroblasts, 125I-LDL assays - results - 20-90% LDLR activity ---- too much variability, do not use in either BS3 or PS3

Approved on: 2021-06-07

Published on: 2021-06-24

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