Variant: NM_000527.5(LDLR):c.1516G>A (p.Val506Met)

CA034649

251881 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 60f79a3e-a1ff-4f07-a491-924658759805

Approved on: 2024-02-23

Published on: 2024-09-25

HGVS expressions

NM_000527.5:c.1516G>A
NM_000527.5(LDLR):c.1516G>A (p.Val506Met)
NC_000019.10:g.11113692G>A
CM000681.2:g.11113692G>A
NC_000019.9:g.11224368G>A
CM000681.1:g.11224368G>A
NC_000019.8:g.11085368G>A
NG_009060.1:g.29312G>A
ENST00000252444.10:c.1774G>A
ENST00000559340.2:c.1516G>A
ENST00000560467.2:c.1396G>A
ENST00000558518.6:c.1516G>A
ENST00000252444.9:c.1770G>A
ENST00000455727.6:c.1012G>A
ENST00000535915.5:c.1393G>A
ENST00000545707.5:c.1135G>A
ENST00000557933.5:c.1516G>A
ENST00000558013.5:c.1516G>A
ENST00000558518.5:c.1516G>A
ENST00000559340.1:c.237G>A
NM_000527.4:c.1516G>A
NM_001195798.1:c.1516G>A
NM_001195799.1:c.1393G>A
NM_001195800.1:c.1012G>A
NM_001195803.1:c.1135G>A
NM_001195798.2:c.1516G>A
NM_001195799.2:c.1393G>A
NM_001195800.2:c.1012G>A
NM_001195803.2:c.1135G>A

Uncertain Significance

• Met criteria codes: PP3

• Not Met criteria codes: PVS1 BS2 BS4 BS3 BS1 BP2 BP3 BP4 PM6 PM2 PM3 PM1 PM4 PM5 PS2 PS4 PS3 PS1 PP4 PP1 BA1

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1516G>A (p.Val506Met) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PP3: REVEL=0.757.

Met criteria codes

• PP3: REVEL=0.757. It is above 0.75, so PP3 is met.

Not Met criteria codes

• PVS1: Not a null variant (nonsense, frameshift, canonical +/- 1 or 2 splice sites, initiation codon, single or multiexon deletion)
• BS2: No data available.
• BS4: No data available.
• BS3: No data available.
• BS1: FAF = 0.0004174 (0.04174%) in East Asian exomes (gnomAD v2.1.1).
• BP2: No data available.
• BP3: No in-frame deletions/insertions
• BP4: REVEL=0.757. It is above 0.5
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: PopMax MAF = 0.00071 (0.071%) in East Asian exomes+genomes (gnomAD v2.1.1).
• PM3: No data available.
• PM1: Variant doesn't meet PM2, is not on exon 4, and is not a cysteine residue.
• PM4: No in-frame deletions/insertions
• PM5: 1 other missense variants in the same codon: - NM_000527.5(LDLR):c.1516G>C (p.Val506Leu) (ClinVar ID 926176) - Uncertain significance by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: Variant doesn't meet PM2.
• PS3: No data available.
• PS1: No other missense variant with the same amino acid change
• PP4: Variant doesn't meet PM2.
• PP1: No data available.
• BA1: FAF = 0.0004174 (0.04174%) in East Asian exomes (gnomAD v2.1.1).