Evidence Repository - GenboreeKB

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000527.5(LDLR):c.1277T>C (p.Leu426Pro)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10585383

251763 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 4dcc4075-4393-4110-9cc8-30a1485a0552

Approved on: 2025-01-31

Published on: 2025-03-09

HGVS expressions

NM_000527.5:c.1277T>C

NM_000527.5(LDLR):c.1277T>C (p.Leu426Pro)

NC_000019.10:g.11113368T>C

CM000681.2:g.11113368T>C

NC_000019.9:g.11224044T>C

CM000681.1:g.11224044T>C

NC_000019.8:g.11085044T>C

NG_009060.1:g.28988T>C

ENST00000252444.10:c.1535T>C

ENST00000559340.2:c.1277T>C

ENST00000560467.2:c.1157T>C

ENST00000558518.6:c.1277T>C

ENST00000252444.9:c.1531T>C

ENST00000455727.6:c.773T>C

ENST00000535915.5:c.1154T>C

ENST00000545707.5:c.896T>C

ENST00000557933.5:c.1277T>C

ENST00000558013.5:c.1277T>C

ENST00000558518.5:c.1277T>C

ENST00000560173.1:n.276T>C

ENST00000560467.1:c.757T>C

NM_000527.4:c.1277T>C

NM_001195798.1:c.1277T>C

NM_001195799.1:c.1154T>C

NM_001195800.1:c.773T>C

NM_001195803.1:c.896T>C

NM_001195798.2:c.1277T>C

NM_001195799.2:c.1154T>C

NM_001195800.2:c.773T>C

NM_001195803.2:c.896T>C

Likely Pathogenic

PP1_Moderate PP3 PP4 PM2 PM3 PS4_Moderate

PS1 PS3 BA1 PM1 PM5 PM4 BS1 BS4 BS3 BS2 BP7 BP4 BP3 BP2 PVS1

Evidence Links 0

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1277T>C (p.Leu426Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4_Moderate, PM2, PM3, PP1_Moderate, PP3 and PP4 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: PopMax MAF = 0.00002229 (0.0022%) in East Asian exomes (gnomAD v4.1.0). So, PM2 is met. PP3: REVEL=0.883. It is above 0.75, so PP3 is met. PS4_Moderate, PP4: Variant meets PM2 and is identified in 9 unrelated index cases (2 cases with DLCN score >=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, France; 5 cases with definite FH by DLCN criteria from U4M - Lille University & CHRU Lille, Université de Lille, France, published on ClinVar; 1 case with possible/definite FH by Simon-Broome criteria in PMID 33269076 (Miroshnikova et al., 2021); 1 case with DLCN score 9 in PMID 9763532 (Mak et al., 1998)). PP1_Moderate: Variant segregates with FH phenotype in 4 informative meioses in 1 family from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, France: 4 affected family members have the variant. PM3: A homozygous proband is reported from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies with LDL of 860 mg/dL.

PP1_Moderate

Variant segregates with FH phenotype in 4 informative meioses in 1 family from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies. So, PP1_Moderate is met.

PP3

REVEL=0.883. It is above 0.75, so PP3 is met.

PP4

Variant meets PM2 and is identified in 7 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.

PM2

PopMax MAF = 0.00002229 (0.0022%) in East Asian exomes (gnomAD v4.1.0). So, PM2 is met.

PM3

A homozygous proband is reported from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies with LDL of 860. So, PM3 is met.

PS4_Moderate

Variant meets PM2 and is identified in 9 unrelated index cases (2 cases with DLCN criteria>=6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies; 5 cases with DLCN criteria of definite FH fromU4M - Lille University & CHRU Lille, Université de Lille, published on ClinVar, 1 case with Simon-Broome criteria of possible/definite FH in PMID: 33269076 (Miroshnikova et al., 2021); 1 case with DLCN 9 in PMID: 9763532 (Mak et al., 1998)). So, PS4_Moderate is met.

PS1

No other missense variant with the same amino acid change.

PS3

No data available.

BA1

PopMax MAF = 0.00002229 (0.0022%) in East Asian exomes (gnomAD v4.1.0).

PM1

Not on exon 4. Not a cysteine residue.

PM5

1 other missense variants in the same codon: - NM_000527.5(LDLR):c.1277T>G (p.Leu426Arg) (ClinVar ID 1120245) - Likely pathogenic by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines.

PM4

No in-frame deletions/insertions

BS1

PopMax MAF = 0.00002229 (0.0022%) in East Asian exomes (gnomAD v4.1.0).

BS4

No data available

BS3

No data available.

BS2

No data available.

BP7

Not a synonymous (silent) variant

BP4

REVEL=0.883. It is above 0.5

BP3

No in-frame deletions/insertions

BP2

No evidence available

PVS1

Not a null variant

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.