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.2149G>A (p.Ala717Thr)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10576330

226387 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: e8646d57-dfbc-413a-95e0-0f3a048b31fd

Approved on: 2025-02-28

Published on: 2025-04-08

HGVS expressions

NM_000527.5:c.2149G>A

NM_000527.5(LDLR):c.2149G>A (p.Ala717Thr)

NC_000019.10:g.11123182G>A

CM000681.2:g.11123182G>A

NC_000019.9:g.11233858G>A

CM000681.1:g.11233858G>A

NC_000019.8:g.11094858G>A

NG_009060.1:g.38802G>A

ENST00000252444.10:c.2407G>A

ENST00000559340.2:c.*218G>A

ENST00000560467.2:c.2029G>A

ENST00000558518.6:c.2149G>A

ENST00000252444.9:c.2403G>A

ENST00000455727.6:c.1645G>A

ENST00000535915.5:c.2026G>A

ENST00000545707.5:c.1615G>A

ENST00000557933.5:c.2149G>A

ENST00000558013.5:c.2149G>A

ENST00000558518.5:c.2149G>A

NM_000527.4:c.2149G>A

NM_001195798.1:c.2149G>A

NM_001195799.1:c.2026G>A

NM_001195800.1:c.1645G>A

NM_001195803.1:c.1615G>A

NM_001195798.2:c.2149G>A

NM_001195799.2:c.2026G>A

NM_001195800.2:c.1645G>A

NM_001195803.2:c.1615G>A

Uncertain Significance

BP4 PM2

PP4 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.2149G>A (p.Ala717Thr) 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: PopMax MAF = 0.00002229 (0.002229%) in East Asian exomes (gnomAD v4.1.0). BP4: REVEL = 0.384, it is below 0.50, splicing evaluation needed. Functional data on splicing not available. A) variant not on limits. B) variant does not create AG/GT. C) there is a AG nearby. MES scores: variant cryptic = -16.32. wt cryptic = -14.92. Canonical acceptor = 8.76. De novo score is negative, so it is not used. Variant is not predicted to alter splicing.

BP4

BP4 - REVEL = 0.384, it is below 0.50, splicing evaluation needed. Functional data on splicing not available. A) variant not on limits. B) variant does not create AG/GT C) there is a AG nearby MES scores. variant cryptic = -16.32. wt cryptic = -14.92. Canonical acceptor = 8.76. De novo score is negative, so it is not used. Variant is not predicted to alter splicing.

PM2

PopMax MAF = 0.00002229 (0.002229 %) in East Asian exomes (gnomAD v4.1.0).

PP4

One FH patient is reported to carry this variant, however, the reported DLCN score only meets five points (Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA). This does not meet the PP4 requirement of the VCEP for a proband to meet a DLCN 6 or greater.

PM5

Although there are other variants reported in the same codon, none are classified as Pathogenic by these guidelines.

Curation History

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