Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

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

CA10585504

251900 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
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
More

Likely Pathogenic

Met criteria codes 4
PM5 PM2 PP1_Strong PP3
Not Met criteria codes 18
PM3 PM1 PM6 BS2 BS3 BS1 BS4 BP2 BP4 BP1 BP5 BA1 PS2 PS3 PS4 PS1 PP4 PP2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
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
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).
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
Not Met criteria codes
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.
PM6
No de novo cases were identified
BS2
Variant not identified in normolipidemic individuals
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.
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
BP5
not applicable
BA1
This variant is absent from gnomAD (v2.1.1).
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.
PP4
PP4_Not Met : Variant meets PM2 but clinical criteria of patients are not available.
PP2
Not applicable
Curation History
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