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.862G>A (p.Glu288Lys)

CA023783

161268 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: dbff12fe-9b22-41d6-9fbd-31ef930eaeb1

Approved on: 2021-06-08

Published on: 2021-06-24

HGVS expressions

NM_000527.5:c.862G>A

NM_000527.5(LDLR):c.862G>A (p.Glu288Lys)

ENST00000558518.6:c.862G>A

ENST00000252444.9:n.1116G>A

ENST00000455727.6:c.358G>A

ENST00000535915.5:c.739G>A

ENST00000545707.5:c.481G>A

ENST00000557933.5:c.862G>A

ENST00000558013.5:c.862G>A

ENST00000558518.5:c.862G>A

ENST00000558528.1:n.377G>A

ENST00000560467.1:n.462G>A

NM_000527.4:c.862G>A

NM_001195798.1:c.862G>A

NM_001195799.1:c.739G>A

NM_001195800.1:c.358G>A

NM_001195803.1:c.481G>A

NM_001195798.2:c.862G>A

NM_001195799.2:c.739G>A

NM_001195800.2:c.358G>A

NM_001195803.2:c.481G>A

NC_000019.10:g.11107436G>A

CM000681.2:g.11107436G>A

NC_000019.9:g.11218112G>A

CM000681.1:g.11218112G>A

NC_000019.8:g.11079112G>A

NG_009060.1:g.23056G>A

Pathogenic

PP4 PP3 PS3_Supporting PM2 PP1_Strong PS4_Moderate

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

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.862G>A (p.Glu288Lys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_Strong, PM2, PS4_Moderate, PP3, PP4 and PS3_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: PP1_strong - variant segregates with FH phenotype in 13 informative meiosis in at least 6 families from different labs. PM2 - PopMax MAF = 0.0001960 (0.0196%) in South Asian exomes (gnomAD v2.1.1). PS4_moderate - Variant meets PM2. Variant identified in at least 7 unrelated index cases with Simon-Broome criteria for FH from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge. PP3 - REVEL = 0.85. PP4 - Variant meets PM2. Identified in 7 unrelated index cases who fulfill Simon-Broome criteria for FH from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. PS3_supporting - Level 3 assays: PMID 21990180: Htz Patient lymphocytes, FACS assays - results - normal (90%) cell surface LDLR, 50% LDL-LDLR binding and 45% LDL uptake ---- results are below 85% of wild-type activity, so PS3_supporting is Met.

PP4

Variant meets PM2. Identified in 7 unrelated index cases who fulfill Simon-Broome criteria for FH from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. ---- PP4 is Met

PP3

REVEL = 0.85. It is above 0.75, so PP3 is Met

PS3_Supporting

Level 3 assays: PMID 21990180: Htz Patient lymphocytes, FACS assays - results - normal (90%) cell surface LDLR, 50% LDL-LDLR binding and 45% LDL uptake ---- results are below 85% of wild-type activity, so PS3_supporting is Met

PM2

PopMax MAF = 0.0001960 (0.0196%) in South Asian exomes (gnomAD v2.1.1). FAF is under 0.02%, so PM2 is Met

PP1_Strong

variant segregates with FH phenotype in 13 informative meiosis in at least 6 families from different labs (Robarts Research Institute and Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge): 10 affected family members have the variant and 3 non-affected family members do not have the variant. --- PP1_Strong is Met

PS4_Moderate

Variant meets PM2. Variant identified in at least 7 unrelated index cases with Simon-Broome criteria for FH from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge. --- PS4_Moderate is Met

BP5

Not applicable

BP7

Missense variant, so BP7 is not applicable

BP2

not identified in individuals with other variants, so BP2 is Not Met

BP3

Not applicable

BP4

REVEL = 0.85. It is not below 0.15 and PP3 is Met, so BP4 is Not Met

BP1

Not applicable

PS2

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

PS1

No more reported missense variants in same codon, PS1 is Not Met

PP2

Not applicable

PM3

not identified in individuals with other variants, so PM3 is Not Met

PM4

Missense variant, not applicable

PM1

Missense at codon 288. PM2 is Met, but it is not exon 4 or any of the 60 Cys residues listed, so PM1 is Not Met

PM5

No more reported missense variants in same codon, PM5 is Not Met

PM6

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

PVS1

Missense variant, PVS1 Not Met

BA1

FAF = 0.00008510 (0.009%) in South Asian exomes (gnomAD v2.1.1). FAF is not above 0.5%, so BA1 is Not Met.

BS3

Level 3 assays: PMID 21990180: Htz Patient lymphocytes, FACS assays - results - normal (90%) cell surface LDLR, 50% LDL-LDLR binding and 45% LDL uptake ---- whole cycle not above 95% of wild-type activity, so BS3_supporting is Not Met

BS1

FAF = 0.00008510 (0.009%) in South Asian 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

BS2

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

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