Variant: NM_000527.5(LDLR):c.1435C>G (p.Leu479Val)

CA404086017

440643 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 1bd2a924-b5f5-4b22-8cd8-b9d296a837e3

Approved on: 2024-02-23

Published on: 2025-02-24

HGVS expressions

NM_000527.5:c.1435C>G
NM_000527.5(LDLR):c.1435C>G (p.Leu479Val)
NC_000019.10:g.11113611C>G
CM000681.2:g.11113611C>G
NC_000019.9:g.11224287C>G
CM000681.1:g.11224287C>G
NC_000019.8:g.11085287C>G
NG_009060.1:g.29231C>G
ENST00000252444.10:c.1693C>G
ENST00000559340.2:c.1435C>G
ENST00000560467.2:c.1315C>G
ENST00000558518.6:c.1435C>G
ENST00000252444.9:c.1689C>G
ENST00000455727.6:c.931C>G
ENST00000535915.5:c.1312C>G
ENST00000545707.5:c.1054C>G
ENST00000557933.5:c.1435C>G
ENST00000558013.5:c.1435C>G
ENST00000558518.5:c.1435C>G
ENST00000559340.1:c.156C>G
ENST00000560467.1:c.915C>G
NM_000527.4:c.1435C>G
NM_001195798.1:c.1435C>G
NM_001195799.1:c.1312C>G
NM_001195800.1:c.931C>G
NM_001195803.1:c.1054C>G
NM_001195798.2:c.1435C>G
NM_001195799.2:c.1312C>G
NM_001195800.2:c.931C>G
NM_001195803.2:c.1054C>G

Uncertain Significance

• Met criteria codes: PM2

• Not Met criteria codes: BS4 BS3 BS1 BS2 BP7 BP2 BP4 PS2 PS4 PS3 PS1 PP4 PP1 PP3 PM3 PM1 PM4 PM5 PM6 PVS1 BA1

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

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1435C>G (p.Leu479Val) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PM2 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: PM2: PopMax MAF = 0.00008 (0.008%) in African exomes (gnomAD v4.0.0).

Met criteria codes

• PM2: PopMax MAF = 0.00008 (.008%) in African exomes (gnomAD version 4.0.0).

Not Met criteria codes

• BS4: Not met.
• BS3: No data available.
• BS1: FAF not present in gnomAD v 2.1.1, so BS1 is not met.
• BS2: Not met.
• BP7: Not a synonymous variant.
• BP2: Not met.
• BP4: REVEL= 0.54
• PS2: Not met.
• PS4: Unknown diagnostic criteria in index case.
• PS3: No data available.
• PS1: Not met.
• PP4: Not met.
• PP1: Not met.
• PP3: REVEL= 0.54. It is not above 0.75, splicing evaluation required. A) Not on limits B) variant is exonic and at least 50bp upstream/downstream from canonical donor site and creates GT MES Scores: de novo variant = -4.99 canonical donor = 5.46 Ratio de novo variant/canonical donor = -4.99/5.46 = -.91 , It is not above 0.9
• PM3: Not met.
• PM1: Not located in exon 4 or at a cysteine residue.
• PM4: Not an in-frame deletion or insertion.
• PM5: Not met.
• PM6: Not met.
• PVS1: Not a null variant.
• BA1: FAF not present in gnomAD v 2.1.1, so BA1 is not met.