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.2150C>G (p.Ala717Gly)

CA10585793

252242 (ClinVar)

Gene: LDLR (HGNC:3949)

Condition: hypercholesterolemia, familial (MONDO:0007750)

Inheritance Mode: Semidominant inheritance

UUID: 31e142d9-6435-42f4-a035-b3d265f4db85

Approved on: 2025-02-28

Published on: 2025-04-08

HGVS expressions

NM_000527.5:c.2150C>G

NM_000527.5(LDLR):c.2150C>G (p.Ala717Gly)

NC_000019.10:g.11123183C>G

CM000681.2:g.11123183C>G

NC_000019.9:g.11233859C>G

CM000681.1:g.11233859C>G

NC_000019.8:g.11094859C>G

NG_009060.1:g.38803C>G

ENST00000252444.10:c.2408C>G

ENST00000559340.2:c.*219C>G

ENST00000560467.2:c.2030C>G

ENST00000558518.6:c.2150C>G

ENST00000252444.9:c.2404C>G

ENST00000455727.6:c.1646C>G

ENST00000535915.5:c.2027C>G

ENST00000545707.5:c.1616C>G

ENST00000557933.5:c.2150C>G

ENST00000558013.5:c.2150C>G

ENST00000558518.5:c.2150C>G

NM_000527.4:c.2150C>G

NM_001195798.1:c.2150C>G

NM_001195799.1:c.2027C>G

NM_001195800.1:c.1646C>G

NM_001195803.1:c.1616C>G

NM_001195798.2:c.2150C>G

NM_001195799.2:c.2027C>G

NM_001195800.2:c.1646C>G

NM_001195803.2:c.1616C>G

Uncertain Significance

PM2 BS3

PP4 PP3 PM5

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.2150C>G (p.Ala717Gly) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2 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: This variant is absent from gnomAD (gnomAD v4.1.0). BS3: Level 1 assays: PMID 12837857 (Chang et al., 2003); Heterologous cells (COS-7), flow cytometry and Western blot assays showed normal (>90%) expression and LDL particle clearance ---- functional study is consistent with no damaging effect.

PM2

This variant is absent from gnomAD (gnomAD v4.1.0).

BS3

BS3 - Level 1 assays: PMID: 12837857: Heterologous cells (COS-7), flow cytometry and western blot assays - result - Normal (>90%) expression and LDL particle clearance ---- functional study is consistent with no damaging effect.

PP4

One FH patient is reported to carry this variant (PMID: 12837857). However, the phenotypic details provided in the paper are not sufficient to meet the VCEP's PP4 criteria. Phenotypic details provided

PP3

PP3 - REVEL = 0.524, it is not above 0.75, splicing evaluation required. Functional data on splicing not available. A) variant not on limits. B) it does not create a AG/GT C) there is an AG nearby. MES scores: variant cryptic = -19.06, wt cryptic = -14.92, canonical acceptor = 8.76. Negatives scores, cryptic sites not used. Variant is not predicted to alter splicing. PP3 is not met.

PM5

There are no variants in the same codon classified as Pathogenic by these guidelines.

Curation History

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