Evidence Repository - Clinical Genome Resources

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.2291T>C (p.Ile764Thr)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA039387

252265 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 9f8b49ba-2fc2-42ca-92af-6bb1301e49a2

Approved on: 2025-02-28

Published on: 2025-04-09

HGVS expressions

NM_000527.5:c.2291T>C

NM_000527.5(LDLR):c.2291T>C (p.Ile764Thr)

NC_000019.10:g.11123324T>C

CM000681.2:g.11123324T>C

NC_000019.9:g.11234000T>C

CM000681.1:g.11234000T>C

NC_000019.8:g.11095000T>C

NG_009060.1:g.38944T>C

ENST00000252444.10:c.2549T>C

ENST00000559340.2:c.*360T>C

ENST00000560467.2:c.2171T>C

ENST00000558518.6:c.2291T>C

ENST00000252444.9:c.2545T>C

ENST00000455727.6:c.1787T>C

ENST00000535915.5:c.2168T>C

ENST00000545707.5:c.1757T>C

ENST00000557933.5:c.2291T>C

ENST00000558013.5:c.2291T>C

ENST00000558518.5:c.2291T>C

NM_000527.4:c.2291T>C

NM_001195798.1:c.2291T>C

NM_001195799.1:c.2168T>C

NM_001195800.1:c.1787T>C

NM_001195803.1:c.1757T>C

NM_001195798.2:c.2291T>C

NM_001195799.2:c.2168T>C

NM_001195800.2:c.1787T>C

NM_001195803.2:c.1757T>C

Likely Benign

BP4 PP4 PM2 BS3

BA1 PS4 PS1 PP1 PP3 PM5 BS2 BS4 BS1

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.2291T>C (p.Ile764Thr) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4, BP4 and BS3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on February 28, 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.0001337 (0.01337%) in East Asian exomes + genomes (gnomAD v4.1.0). PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills Simon Broome criteria for possible FH from Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal, after alternative causes of high cholesterol were excluded. BP4: REVEL = 0.352, it is below 0.50, so splicing evaluation required. Functional data on splicing not available. A) Variant not on limits. B) Does not create GT. C) There is a GT nearby. MES scores: variant cryptic = -5.73, wt cryptic = -8.16, canonical donor site = 9.06. Cryptic scores are negative, splice site not used. Variant is not predicted to alter splicing. BS3: Level 1 assay: PMID 34167030 (Alves et al., 2021): Heterologous cells (CHO), FACS; Result - > Normal cell surface LDLR (105%), LDL-LDLR binding (90%) and uptake (89%). Functional study is consistent with no damaging effect. Level 3 assay: PMID 37719435 (Graça et al., 2023): Heterologous cells (CHO), microscopy assays; Result - >100% LDLR expression and >100% LDLR activity. Functional study is consistent with no damaging effect. With the application of BP4 and BS3 and the functional evidence available, consensus was to classify this variant as Likely Benign.

BP4

REVEL = 0.352, it is below 0.50, so splicing evaluation required. Functional data on splicing not available. A) Variant not on limits B) Does not create GT C) There is a GT nearby. MES scores: variant cryptic = -5.73, wt cryptic = -8.16, canonical donor site = 9.06. Ratio variant cryptic/wt cryptic: -5.73/-8.16 = 0.70 --- it is not above 1.1. Ratio variant cryptic/canonical donor: -5.73/9.06 = -0.63 --- it is not above 0.9. Variant is not predicted to alter splicing.

PP4

Variant meets PM2 and is identified in at least 1 index case who fulfills SB possible for FH from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, after alternative causes of high cholesterol were excluded.

PM2

PopMax MAF = 0.0001337 (0.01337%) in East Asian exomes+genomes (gnomAD v4.1.0).

BS3

Level 1 assays: PMID 37719435: Heterologous cells (CHO), microscopy assays Result - >100% LDLR expression and >100% LDLR activity Functional study is consistent with no damaging effect. Level 1 assays: PMID 34167030: Heterologous cells (CHO), FACS Result - > Normal cell surface LDLR (105%), LDL-LDLR binding (90%) and uptake (89%) Functional study is consistent with no damaging effect.

BA1

FAF = 0.00006511 (0.006511%) in East Asian exomes (gnomAD v4.1.0).

PS4

Variant identified in only 1 FH case

PS1

1 other missense variants in the same codon: - NM_000527.5(LDLR):c.2291T>G (p.Ile764Arg) (ClinVar ID 920005) - Uncertain significance by these guidelines

PP1

Variant was identified in 2 members of 1 family, but data on LDL-C was missing in one of them

PP3

PM5

1 other missense variants in the same codon: - NM_000527.5(LDLR):c.2291T>G (p.Ile764Arg) (ClinVar ID 920005) - Uncertain significance by these guidelines

BS2

Variant was not identified in any controls

BS4

Variant identified in only 1 family member

BS1

FAF = 0.00006511 (0.006511%) in East Asian exomes (gnomAD v4.1.0).

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.