Variant: NM_000527.5(LDLR):c.2389+5G>A

CA10585843

252306 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: df6304d1-7467-43e4-9247-ec974c37229f

Approved on: 2023-03-20

Published on: 2023-03-31

HGVS expressions

NM_000527.5:c.2389+5G>A
NM_000527.5(LDLR):c.2389+5G>A
NC_000019.10:g.11128090G>A
CM000681.2:g.11128090G>A
NC_000019.9:g.11238766G>A
CM000681.1:g.11238766G>A
NC_000019.8:g.11099766G>A
NG_009060.1:g.43710G>A
ENST00000252444.10:c.2647+5G>A
ENST00000559340.2:c.*458+5G>A
ENST00000560467.2:c.2269+5G>A
ENST00000558518.6:c.2389+5G>A
ENST00000252444.9:c.2643+5G>A
ENST00000455727.6:c.1885+5G>A
ENST00000535915.5:c.2266+5G>A
ENST00000545707.5:c.1855+5G>A
ENST00000557933.5:c.2389+5G>A
ENST00000558013.5:c.2389+5G>A
ENST00000558518.5:c.2389+5G>A
ENST00000560628.1:n.108+436G>A
NM_000527.4:c.2389+5G>A
NM_001195798.1:c.2389+5G>A
NM_001195799.1:c.2266+5G>A
NM_001195800.1:c.1885+5G>A
NM_001195803.1:c.1855+5G>A
NM_001195798.2:c.2389+5G>A
NM_001195799.2:c.2266+5G>A
NM_001195800.2:c.1885+5G>A
NM_001195803.2:c.1855+5G>A

Uncertain Significance

• Met criteria codes: PP3 PP4 PM2 PS4_Supporting

• Not Met criteria codes: PP1 PM6 PS1 PS2 PS3 PM1 PM3 PM5 PM4 BA1 BP4 BP3 BP2 BS1 BS4 BS3 BS2

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.2389+5G>A variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes 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: PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated index cases with DLCN criteria>=6 from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation). So PS4_Supporting is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So PM2 is met. PP3: No REVEL, splicing evaluation needed. Functional data on splicing not available. A) variant located -3 to +6 from canonical donor site MES scores: canonical site variant = 4.93; canonical donor wt = 9.86. Ratio: 4.93/9.86 = 0.5 ---- It is below 0.8 Variant is predicted to alter splicing. 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). So PP4 is met.

Met criteria codes

• PP3: No REVEL, splicing evaluation needed. Functional data on splicing not available. A) variant located -3 to +6 from canonical donor site MES scores: canonical site variant = 4.93; canonical donor wt = 9.86. Ratio: 4.93/9.86 = 0.5 ---- It is below 0.8 Variant is predicted to alter splicing. 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). So PP4 is met.
• PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So PM2 is met. So PM2 is met.
• PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated index cases with DLCN criteria>=6 from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation). So PS4_Supporting is met.

Not Met criteria codes

• PP1: Only 1 affected member and 1 informative meiosis.
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: The current variant is in a non-coding region
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: No data available.
• PM1: Not located in exon 4 and not a cysteine residue.
• PM3: No data available.
• PM5: The current variant is in a non-coding region
• PM4: No in-frame deletions/insertions
• BA1: This variant is absent from gnomAD (gnomAD v2.1.1).
• BP4: No REVEL, splicing evaluation needed. Functional data on splicing not available. A) variant located -3 to +6 from canonical donor site MES scores: canonical site variant = 4.93; canonical donor wt = 9.86. Ratio: 4.93/9.86 = 0.5 ---- It is below 0.8 Variant is predicted to alter splicing.
• BP3: No in-frame deletions/insertions
• BP2: No data available.
• BS1: This variant is absent from gnomAD (gnomAD v2.1.1).
• BS4: No data available.
• BS3: No data available.
• BS2: No data available.