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

Variant: NM_000527.5(LDLR):c.1277T>G (p.Leu426Arg)

CA404084869

1120245 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 787b1bbb-1f79-47d7-8bbe-10a057c1522a
Approved on: 2025-01-31
Published on: 2025-03-09

HGVS expressions

NM_000527.5:c.1277T>G
NM_000527.5(LDLR):c.1277T>G (p.Leu426Arg)
NC_000019.10:g.11113368T>G
CM000681.2:g.11113368T>G
NC_000019.9:g.11224044T>G
CM000681.1:g.11224044T>G
NC_000019.8:g.11085044T>G
NG_009060.1:g.28988T>G
ENST00000252444.10:c.1535T>G
ENST00000559340.2:c.1277T>G
ENST00000560467.2:c.1157T>G
ENST00000558518.6:c.1277T>G
ENST00000252444.9:c.1531T>G
ENST00000455727.6:c.773T>G
ENST00000535915.5:c.1154T>G
ENST00000545707.5:c.896T>G
ENST00000557933.5:c.1277T>G
ENST00000558013.5:c.1277T>G
ENST00000558518.5:c.1277T>G
ENST00000560173.1:n.276T>G
ENST00000560467.1:c.757T>G
NM_000527.4:c.1277T>G
NM_001195798.1:c.1277T>G
NM_001195799.1:c.1154T>G
NM_001195800.1:c.773T>G
NM_001195803.1:c.896T>G
NM_001195798.2:c.1277T>G
NM_001195799.2:c.1154T>G
NM_001195800.2:c.773T>G
NM_001195803.2:c.896T>G
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Likely Pathogenic

Met criteria codes 5
PS4_Supporting PP1 PP4 PP3 PM2
Not Met criteria codes 18
BP2 BP3 BP4 BP7 BS2 BS4 BS3 BS1 PS2 PS3 PS1 PVS1 PM6 PM3 PM4 PM1 PM5 BA1

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

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Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.1277T>G (p.Leu426Arg) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP1, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on January 31, 2025. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.1.0). PP3: REVEL= 0.907. It is above 0.75, so PP3 is met. PS4_Supporting, PP4: Variant meets PM2. Identified in 3 unrelated cases (1 case from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France with possible FH by Simon Broome criteria; 1 case with DLCN score of 6 from Lille University & CHRU Lille, France; 1 case with definite FH by Simon Broome criteria from Centre Hospitalo-Universitaire Xavier Bichat, Paris, France). PP1: Variant segregates with FH phenotype in 2 informative meioses identified by Centre Hospitalo-Universitaire Xavier Bichat, Paris.
Met criteria codes
PS4_Supporting
Variant meets PM2. Identified in 3 unrelated cases (1 case from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France with Simon Broome criteria of possible FH, 1 case from Lille University & CHRU Lille with DLCN of 6, and 1 case from Centre Hospitalo-Universitaire Xavier Bichat, Paris with Simon Broome criteria of definite FH.) So, PS4_Supporting is met.
PP1
Variant segregates with FH phenotype in 2 informative meioses identified by Centre Hospitalo-Universitaire Xavier Bichat, Paris. So, PP1 is met.
PP4
Variant meets PM2 and is identified in 3 unrelated index cases who fulfill clinical criteria for FH from several labs (see PS4 for details), after alternative causes of high cholesterol were excluded. So, PP4 is met.
PP3
REVEL= 0.907. It is above 0.75, so PP3 is met.
PM2
This variant is absent from gnomAD (gnomAD v4.1.0). So, PM2 is met.
Not Met criteria codes
BP2
No data available.
BP3
No in-frame deletions/insertions.
BP4
REVEL= 0.907. It is above 0.5.
BP7
Not a synonymous variant.
BS2
No data available.
BS4
No data available.
BS3
No data available.
BS1
This variant is absent from gnomAD (gnomAD v4.1.0).
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No data available.
PS1
No other missense variant with the same amino acid change.
PVS1
Not a null variant.
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No data available.
PM4
No in-frame deletions/insertions.
PM1
Not on exon 4. Not a cysteine residue.
PM5
1 other missense variants in the same codon: - NM_000527.5(LDLR):c.1277T>C (p.Leu426Pro) (ClinVar ID 251763) - Likely Pathogenic by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.
BA1
This variant is absent from gnomAD (gnomAD v4.1.0).
Curation History
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