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]

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Variant: NM_000527.5(LDLR):c.846C>A (p.Phe282Leu)

CA023778

183098 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 793a906e-889c-4bc4-8d0b-c59588d0f381

Approved on: 2023-04-28

Published on: 2023-04-30

HGVS expressions

NM_000527.5:c.846C>A

NM_000527.5(LDLR):c.846C>A (p.Phe282Leu)

NC_000019.10:g.11107420C>A

CM000681.2:g.11107420C>A

NC_000019.9:g.11218096C>A

CM000681.1:g.11218096C>A

NC_000019.8:g.11079096C>A

NG_009060.1:g.23040C>A

ENST00000558518.6:c.846C>A

ENST00000252444.9:n.1100C>A

ENST00000455727.6:c.342C>A

ENST00000535915.5:c.723C>A

ENST00000545707.5:c.465C>A

ENST00000557933.5:c.846C>A

ENST00000558013.5:c.846C>A

ENST00000558518.5:c.846C>A

ENST00000558528.1:n.361C>A

ENST00000560467.1:n.446C>A

NM_000527.4:c.846C>A

NM_001195798.1:c.846C>A

NM_001195799.1:c.723C>A

NM_001195800.1:c.342C>A

NM_001195803.1:c.465C>A

NM_001195798.2:c.846C>A

NM_001195799.2:c.723C>A

NM_001195800.2:c.342C>A

NM_001195803.2:c.465C>A

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PS3_Supporting PP4 PP3 PS4_Supporting PM2

PVS1 BA1 BP2 BP3 BP4 BS2 BS4 BS1 PP1 PM5 PM3 PM1 PM4 PM6 PS1 PS2

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.846C>A (p.Phe282Leu) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3_Supporting, PS4_Supporting, PM2, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS3_Supporting: Level 3 assays: PMID 25647241: HeLa cells, In vitro microscopy assays - result - 66% wild type LDLR expression (below 70%, Figure 3). ---- functional study is consistent with damaging effect. So, PS3_Supporting is met. PS4_Supporting: Variants meets PM2 and is identified in 2 cases from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille with diagnosis of probable FH based on DLCN criteria. So, PS4_Supporting is met. PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes (gnomAD v2.1.1). So, PM2 is met. PP3: REVEL=0.877. It is above 0.75, so PP3 is met. PP4: Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details), after alternative causes for high cholesterol were excluded.

PS3_Supporting

Level 3 assays: PMID 25647241: HeLa cells, In vitro microscopy assays - result - 66% wild type LDLR expression (below 70%, Figure 3). ---- functional study is consistent with damaging effect. So, PS3_Supporting is met.

PP4

Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH (see PS4 for details), after alternative causes for high cholesterol were excluded.

PP3

REVEL=0.877. It is above 0.75, so PP3 is met

PS4_Supporting

Variants meets PM2 and is identified in 2 cases from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille with diagnosis of probable FH based on DLCN criteria. So, PS4_Supporting is met.

PM2

PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes (gnomAD v2.1.1). So, PM2 is met.

PVS1

Not a null variant

BA1

PopMax FAF= 0.000003977

BP2

No data available

BP3

No in-frame deletions/insertions

BP4

REVEL=0.877 (>0.5).

BS2

No data available.

BS4

No data available.

BS1

PopMax FAF= 0.000003977

PP1

No data available.

PM5

3 other missense variants in the same codon: - NM_000527.5(LDLR):c.845T>A (p.Phe282Tyr) (ClinVar ID 1763461) - Uncertain significance by these guidelines - NM_000527.5(LDLR):c.845T>C (p.Phe282Ser) (ClinVar ID 1466547) - Uncertain significance by these guidelines - NM_000527.5(LDLR):c.845T>G (p.Phe282Cys) (ClinVar ID 977997) - Uncertain significance by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.

PM3

No data available

PM1

Not in exon 4. Not a cysteine residue.

PM4

No in-frame deletions/insertions

PM6

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS1

One more missense variant that leads to the same amino acid change: - NM_000527.5(LDLR):c.844T>C (p.Phe282Leu) (ClinVar ID 977996) - classified as uncertain significance by these guidelines

PS2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

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