Variant: NM_000527.4(LDLR):c.-217C>T

CA10584691

250927 (ClinVar)

Gene: N/A

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 39f1f763-d020-4c98-b299-b417769cbe17

Approved on: 2023-11-07

Published on: 2024-09-25

HGVS expressions

NM_000527.4(LDLR):c.-217C>T
NC_000019.10:g.11089332C>T
CM000681.2:g.11089332C>T
NC_000019.9:g.11200008C>T
CM000681.1:g.11200008C>T
NC_000019.8:g.11061008C>T
NG_009060.1:g.4952C>T
NR_163945.1:n.328G>A

Benign

• Met criteria codes: BS3_Supporting BA1

• Not Met criteria codes: BP2 BP3 BP4 BS2 BS4 BS1 PP1 PP4 PP3 PM6 PM2 PM3 PM1 PM4 PM5 PS2 PS4 PS3 PS1 PVS1

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.4(LDLR):c.-217C>T variant is classified as Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BA1 and BS3_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: BA1: FAF=0.01016 (1.016%) in African/African American Genomes (gnomAD v4.0.0). BS3_Supporting: Level 3 assay: PMID 10484771 (Scholtz CL et al., 1999): Heterologous cells (HepG2). Luciferase assays demonstrated 160% gene expression ---- functional study is consistent with no damaging effect.

Met criteria codes

• BS3_Supporting: Level 3 assays - PMID 10484771: Heterologous cells (HepG2), luciferase assays - results - 160% gene expression. So, BS3_Supporting is met.
• BA1: FAF=0.01016 (1.016%) in African/African American Genomes (gnomAD v4.0.0). So, BA1 is met.

Not Met criteria codes

• BP2: No data available
• BP3: No in-frame deletions/insertions
• BP4: Variant is in the promoter region
• BS2: No data available
• BS4: No data available
• BS1: FAF=0.01016 (1.016%) in African/African American Genomes (gnomAD v4.0.0).
• PP1: No data available
• PP4: Variant does not meet PM2. So, PP4 is not met.
• PP3: Variant is in the promoter region
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: FAF=0.01016 (1.016%) in African/African American Genomes (gnomAD v4.0.0).
• PM3: No data available
• PM1: Not in exon 4. Not a cysteine residue
• PM4: No in-frame deletions/insertions
• PM5: Variant is in the promoter region
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: Variant does not meet PM2. So, PS4 is not met.
• PS3: Level 3 assays - PMID 10484771: Heterologous cells (HepG2), luciferase assays - results - 160% gene expression.
• PS1: Variant is in the promoter region
• PVS1: Not a null variant