Variant: NM_000527.5(LDLR):c.1436T>A (p.Leu479Gln)

CA404086021

992900 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: cfded3a1-2932-4f02-9c54-0a202f10c204

Approved on: 2024-02-23

Published on: 2025-02-24

HGVS expressions

NM_000527.5:c.1436T>A
NM_000527.5(LDLR):c.1436T>A (p.Leu479Gln)
NC_000019.10:g.11113612T>A
CM000681.2:g.11113612T>A
NC_000019.9:g.11224288T>A
CM000681.1:g.11224288T>A
NC_000019.8:g.11085288T>A
NG_009060.1:g.29232T>A
ENST00000252444.10:c.1694T>A
ENST00000559340.2:c.1436T>A
ENST00000560467.2:c.1316T>A
ENST00000558518.6:c.1436T>A
ENST00000252444.9:c.1690T>A
ENST00000455727.6:c.932T>A
ENST00000535915.5:c.1313T>A
ENST00000545707.5:c.1055T>A
ENST00000557933.5:c.1436T>A
ENST00000558013.5:c.1436T>A
ENST00000558518.5:c.1436T>A
ENST00000559340.1:c.157T>A
ENST00000560467.1:c.916T>A
NM_000527.4:c.1436T>A
NM_001195798.1:c.1436T>A
NM_001195799.1:c.1313T>A
NM_001195800.1:c.932T>A
NM_001195803.1:c.1055T>A
NM_001195798.2:c.1436T>A
NM_001195799.2:c.1313T>A
NM_001195800.2:c.932T>A
NM_001195803.2:c.1055T>A

Likely Pathogenic

• Met criteria codes: PP4 PP3 PM3 PM2 PS4_Supporting PP1_Moderate

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

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.1436T>A (p.Leu479Gln) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PM3, PP1_Moderate, PP3, PP4 and PS4_Supporting 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: This variant is absent from gnomAD v4.0.0. PP3: REVEL= 0.938. PS4_Supporting, PP4: Identified in two index cases who fulfil FH criteria, reported in PMID 33732287 (Moradi et al., 2021; LDLC 391 mg/dl at age of 24 years) and PMID 29213121 (Fairoozy et al., 2017; LDL-C 15 mmol/L at age of 15 years). Both index cases are homozygous for the variant. PP1_Moderate: Variant segregates with FH phenotype in five informative meiosis in two families, the affected relatives are positive for the variant, reported in PMID 33732287 and 29213121. PM3: Variant observed in a true homozygous case who had HoFH phenotype with LDLC of 15 mmol/L, reported in PMID 29213121.

Met criteria codes

• PP4: Identified in two index cases who fulfil FH criteria, reported in PMID 33732287 (LDLC 391 mg/dl at age of 24) and PMID 29213121 (LDL-C 15 mmol/L at age of 15). Both index cases are homozygous for the variant.
• PP3: REVEL= 0.938
• PM3: Variant observed in a true homozygous case who had HoFH phenotype with LDLC of 15 mmol/l, reported in PMID 29213121
• PM2: This variant is absent from gnomAD v4.0.0
• PS4_Supporting: Identified in two index cases who fulfil FH criteria, reported in PMID 33732287 (LDLC 391 mg/dl at age of 24) and PMID 29213121 (LDL-C 15 mmol/L at age of 15). Both index cases are homozygous for the variant.
• PP1_Moderate: Variant segregates with FH phenotype in five informative meiosis in two families, the affected relatives are positive for the variant, reported in PMID 33732287 and 29213121.

Not Met criteria codes

• BS4: Not met.
• BS3: No data available.
• BS1: Variant absent from gnomAD v2.1.1
• BS2: Not met.
• BP7: Not a synonymous variant.
• BP2: Not met.
• BP4: REVEL= 0.938
• PS2: Not met.
• PS3: No data available.
• PS1: No other pathogenic variants at same codon leading to same amino acid change.
• BA1: Variant absent from gnomAD v2.1.1
• PM1: Not located in exon 4 or at a cysteine residue.
• PM4: Not an in-frame deletion/insertion.
• PM5: No other pathogenic variants at same codon leading to different amino acid change.
• PM6: Not met.
• PVS1: Not a null variant.