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>G (p.Ile764Arg)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA404095729

920005 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 105f69e7-5cca-4f55-a074-f15d81674431

Approved on: 2025-02-28

Published on: 2025-04-09

HGVS expressions

NM_000527.5:c.2291T>G

NM_000527.5(LDLR):c.2291T>G (p.Ile764Arg)

NC_000019.10:g.11123324T>G

CM000681.2:g.11123324T>G

NC_000019.9:g.11234000T>G

CM000681.1:g.11234000T>G

NC_000019.8:g.11095000T>G

NG_009060.1:g.38944T>G

ENST00000252444.10:c.2549T>G

ENST00000559340.2:c.*360T>G

ENST00000560467.2:c.2171T>G

ENST00000558518.6:c.2291T>G

ENST00000252444.9:c.2545T>G

ENST00000455727.6:c.1787T>G

ENST00000535915.5:c.2168T>G

ENST00000545707.5:c.1757T>G

ENST00000557933.5:c.2291T>G

ENST00000558013.5:c.2291T>G

ENST00000558518.5:c.2291T>G

NM_000527.4:c.2291T>G

NM_001195798.1:c.2291T>G

NM_001195799.1:c.2168T>G

NM_001195800.1:c.1787T>G

NM_001195803.1:c.1757T>G

NM_001195798.2:c.2291T>G

NM_001195799.2:c.2168T>G

NM_001195800.2:c.1787T>G

NM_001195803.2:c.1757T>G

Uncertain Significance

PM2 BP4

PS1 PP3 PM5 BS1 BA1

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>G (p.Ile764Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 and BP4 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: Variant is absent from gnomAD v4.1.0 BP4: REVEL = 0.433, it is below 0.50, so splicing evaluation required. Functional data on splicing not available. A) not on limits. B) Variant does not create GT. C) There is a GT nearby. MES scores: variant cryptic = -7.17, wt cryptic = -8.16, canonical donor site = 9.06. Cryptic scores are negative, splice site not used. Variant is not predicted to alter splicing.

PM2

Variant is absent in gnomAD v4.1.0

BP4

REVEL = 0.433, it is below 0.50, so splicing evaluation required. Functional data on splicing not available. A) not on limits B) Variant does not create GT C) There is a GT nearby MES scores: variant cryptic = -7.17, wt cryptic = -8.16, canonical donor site = 9.06. Ratio variant cryptic/wt cryptic: -7.17/-8.16 = 0.88 --- it is not above 1.1. Ratio variant cryptic/canonical donor: -7.17/9.06 = -0.79 --- it is not above 0.9. Variant is not predicted to alter splicing.

PS1

No variants causing the same amino acid change classified as Pathogenic by these guidelines.

PP3

PM5

:1 other missense variants in the same codon: - NM_000527.5(LDLR):c.2291T>C (p.Ile764Thr) (ClinVar ID 252265) - Likely benign by these guidelines There are no variants in the same codon classified as Pathogenic by these guidelines.

BS1

Variant is absent in gnomAD v4.1.0

BA1

Variant is absent in gnomAD v4.1.0

Curation History

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