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: PS1 PS2 PS3 PS4 PP1 PP3 PP4 PVS1 PM1 PM3 PM5 PM4 PM6 PM2 BS2 BS1 BS4 BP4 BP3 BP2

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

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