Variant: NM_000527.5(LDLR):c.1567G>T (p.Val523Leu)

CA10585504

251900 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 26373548-6259-48c4-9a6c-0d1ed62bb223

Approved on: 2023-01-27

Published on: 2024-10-07

HGVS expressions

NM_000527.5:c.1567G>T
NM_000527.5(LDLR):c.1567G>T (p.Val523Leu)
NC_000019.10:g.11113743G>T
CM000681.2:g.11113743G>T
NC_000019.9:g.11224419G>T
CM000681.1:g.11224419G>T
NC_000019.8:g.11085419G>T
NG_009060.1:g.29363G>T
ENST00000252444.10:c.1825G>T
ENST00000559340.2:c.1567G>T
ENST00000560467.2:c.1447G>T
ENST00000558518.6:c.1567G>T
ENST00000252444.9:c.1821G>T
ENST00000455727.6:c.1063G>T
ENST00000535915.5:c.1444G>T
ENST00000545707.5:c.1186G>T
ENST00000557933.5:c.1567G>T
ENST00000558013.5:c.1567G>T
ENST00000558518.5:c.1567G>T
ENST00000559340.1:c.288G>T
NM_000527.4:c.1567G>T
NM_001195798.1:c.1567G>T
NM_001195799.1:c.1444G>T
NM_001195800.1:c.1063G>T
NM_001195803.1:c.1186G>T
NM_001195798.2:c.1567G>T
NM_001195799.2:c.1444G>T
NM_001195800.2:c.1063G>T
NM_001195803.2:c.1186G>T

Likely Pathogenic

• Met criteria codes: PP1_Strong PP3 PM5 PM2

• Not Met criteria codes: BA1 BP5 BP2 BP4 BP1 BS3 BS1 BS4 BS2 PP4 PP2 PM3 PM1 PS2 PS3 PS4 PS1 PM6

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.1567G>T (p.Val523Leu) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PP1_Strong, PM2, PM5 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 27 January 2023. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (v2.1.1). PP3: REVEL = 0.904. PM5: There is 1 missense variant in the same codon, NM_000527.5(LDLR):c.1567G>A (p.Val523Met), classified as Pathogenic by these guidelines. PP1_Strong: Variant segregates with FH phenotype in 7 informative meioses from 1 family from Laboratory of Genetics and Molecular Cardiology, Brazil.

Met criteria codes

• PP1_Strong: PP1_strong: Variant segregates with FH phenotype in 7 informative meiosis from 1 family from Laboratory of Genetics and Molecular Cardiology.
• PP3: PP3_Met : REVEL = 0.904
• PM5: PM5_Met : There is 1 missense variant in the same codon (NM_000527.5(LDLR):c.1567G>A (p.Val523Met)) classified as Pathogenic by these guidelines.
• PM2: PM2_Met : This variant is absent from gnomAD (v2.1.1).

Not Met criteria codes

• BA1: This variant is absent from gnomAD (v2.1.1).
• BP5: not applicable
• BP2: Variant meets PM2 but is not identified in an index case with heterozygous or homozygous FH phenotype as well as LDLR variant, in trans, or APOB/PCSK9 variant classified as Pathogenic by these or general ACMG guidelines.
• BP4: REVEL = 0.904. Score is not below 0.50.
• BP1: Not applicable
• BS3: No functional assays performed/found
• BS1: This variant is absent from gnomAD (v2.1.1).
• BS4: No instance of variant non-segregation with FH phenotype in at least 2 informative meiosis from at least 2 families with at least one unaffected relative (LDL-C <50th centile) who is positive for the variant.
• BS2: Variant not identified in normolipidemic individuals
• PP4: PP4_Not Met : Variant meets PM2 but clinical criteria of patients are not available.
• PP2: Not applicable
• PM3: Variant meets PM2 but is not identified in an index case with heterozygous or homozygous FH phenotype as well as LDLR variant, in trans, or APOB/PCSK9 variant classified as Pathogenic by these or general ACMG guidelines.
• PM1: Variant meets PM2 but it is in exon 10. Not applicable.
• PS2: No de novo cases were identified
• PS3: No functional assays performed/found
• PS4: PS4_Not Met : Variant meets PM2 and is identified in 3 patients (1 from Laboratory of Genetics and Molecular Cardiology, 1 in PMID: 20809525 and 1 in PMID: 15199436) but clinical criteria are not available.
• PS1: PS1_Not Met : There is one missense variant that leads to the same aminoacid change (c.1567G>C (p.Val523Leu)) but it is not classified as pathogenic by these guidelines.
• PM6: No de novo cases were identified