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]

Variant: NM_000527.5(LDLR):c.-13A>G

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA085167

250964 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 3d74c398-d51d-4ad8-b608-3a55c7a57b51

Approved on: 2024-10-28

Published on: 2025-02-07

HGVS expressions

NM_000527.5:c.-13A>G

NM_000527.5(LDLR):c.-13A>G

NC_000019.10:g.11089536A>G

CM000681.2:g.11089536A>G

NC_000019.9:g.11200212A>G

CM000681.1:g.11200212A>G

NC_000019.8:g.11061212A>G

NG_009060.1:g.5156A>G

ENST00000559340.2:c.-13A>G

ENST00000560467.2:c.-13A>G

ENST00000558518.6:c.-13A>G

ENST00000455727.6:c.-13A>G

ENST00000535915.5:c.-13A>G

ENST00000545707.5:c.-13A>G

ENST00000557933.5:c.-13A>G

ENST00000557958.1:n.74A>G

ENST00000558013.5:c.-13A>G

ENST00000558518.5:c.-13A>G

ENST00000560502.5:n.74A>G

NM_000527.4:c.-13A>G

NM_001195798.1:c.-13A>G

NM_001195799.1:c.-13A>G

NM_001195800.1:c.-13A>G

NM_001195803.1:c.-13A>G

NM_001195798.2:c.-13A>G

NM_001195799.2:c.-13A>G

NM_001195800.2:c.-13A>G

NM_001195803.2:c.-13A>G

NR_163945.1:n.124T>C

Uncertain Significance

PM2 BS3_Supporting PP4

PM3 PM1 PM4 PM5 PM6 BA1 BS2 BS4 BS1 BP2 BP3 BP4 PS2 PS4 PS3 PS1 PP1 PP3

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

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Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.-13A>G variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4, and BS3_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on October 28th, 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.00002374 (0.0023%) in European (Non-Finnish) exomes+genomes (gnomAD v4.1.0). BS3_Supporting: Level 3 assays - PMID 25248394 (Khamis et al., 2015): Heterologous cells (Huh7), Luciferase assays: results - normal (96%) gene expression. PMID 31395865 (Kircher et al., 2019): Heterologous cells (HepG2), luciferase assays: results - 97-106% gene expression. So, BS3_Supporting is met. PP4: Variant meets PM2 and is identified in 1 case meeting Simon Broome criteria from the Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal, after alternative causes of high cholesterol were excluded.

PM2

PopMax MAF = 0.00002374 (0.0023%) in European (Non-Finnish) exomes+genomes (gnomAD v4.1.0). So, PM2 is met.

BS3_Supporting

Level 3 assays - PMID 25248394: Heterologous cells (Huh7), Luciferase assays: results - normal (96%) gene expression. PMID 31395865: Heterologous cells (HepG2), luciferase assays: results - 97-106% gene expression. So, BS3_Supporting is met.

PP4

Variant meets PM2. Identified in 1 FH case from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge (Portugal) with Simon Broome criteria, after alternative causes of high cholesterol were excluded. So, PP4 is met.

PM3

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

PM1

Not on exon 4. Not a cysteine residue

PM4

No in-frame deletions/insertions

PM5

Variant is In the 5 prime UTR (non-coding region).

PM6

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

BA1

FAF = 0.00001919 (0.0019%) in European (Non-Finnish) exomes+genomes (gnomAD v4.1.0).

BS2

No data available

BS4

2 family members from 1 family negative for variant with LDL-C >75th from Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge.

BS1

FAF = 0.00001919 (0.0019%) in European (Non-Finnish) exomes+genomes (gnomAD v4.1.0).

BP2

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

BP3

No in-frame deletions/insertions

BP4

Variant is In the 5 prime UTR (non-coding region). No REVEL available.

PS2

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

PS4

PS3

Level 3 assays - PMID 25248394: Heterologous cells (Huh7), Luciferase assays: results - normal (96%) gene expression.

PS1

Variant is In the 5 prime UTR (non-coding region).

PP1

Variant segregates with FH phenotype in 2 informative meioses in 1 family identified by Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge. However, nonsegregation is also present (2 family members negative for variant with LDL-C >75th). Thus, PP1 Is not used.

PP3

Variant is In the 5 prime UTR (non-coding region). No REVEL available.

Curation History

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