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.2039T>C (p.Leu680Pro)

CA404093609

440674 (ClinVar)

Gene: LDLR (HGNC:3949)

Condition: hypercholesterolemia, familial (MONDO:0007750)

Inheritance Mode: Semidominant inheritance

UUID: 7682bb41-edcc-47f6-b8f4-5b1f2c9f8d26

Approved on: 2025-07-11

Published on: 2025-10-08

HGVS expressions

NM_000527.5:c.2039T>C

NM_000527.5(LDLR):c.2039T>C (p.Leu680Pro)

NC_000019.10:g.11120421T>C

CM000681.2:g.11120421T>C

NC_000019.9:g.11231097T>C

CM000681.1:g.11231097T>C

NC_000019.8:g.11092097T>C

NG_009060.1:g.36041T>C

ENST00000252444.10:c.2297T>C

ENST00000559340.2:c.*108T>C

ENST00000560467.2:c.1919T>C

ENST00000558518.6:c.2039T>C

ENST00000252444.9:c.2293T>C

ENST00000455727.6:c.1535T>C

ENST00000535915.5:c.1916T>C

ENST00000545707.5:c.1606+188T>C

ENST00000557933.5:c.2039T>C

ENST00000558013.5:c.2039T>C

ENST00000558518.5:c.2039T>C

NM_000527.4:c.2039T>C

NM_001195798.1:c.2039T>C

NM_001195799.1:c.1916T>C

NM_001195800.1:c.1535T>C

NM_001195803.1:c.1606+188T>C

NM_001195798.2:c.2039T>C

NM_001195799.2:c.1916T>C

NM_001195800.2:c.1535T>C

NM_001195803.2:c.1606+188T>C

Uncertain Significance

PP3 PP4 PM2

PS4 PP1 PM1

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.2039T>C (p.Leu680Pro) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 11 July 2025. The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v4.1.0). PM3: REVEL score = 0.918. PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills MEDPED criteria for FH from PMID 27824480 (Gabčová et al., 2017), Slovakia, after alternative causes of high cholesterol were excluded.

PP3

REVEL score = 0.918 so PP3 is met.

PP4

PP4_Met: Variant meets PM2 and was identified in 2 related patients who fulfil clinical criteria for FH (MEDPED criteria) from PMID: 27824480, after alternative causes of high cholesterol are excluded

PM2

PM2_Met: This variant is absent from gnomAD (gnomAD v4.1.0);

PS4

PS4_Not Met: the variant meets PM2 but was identified in 2 related patients who fulfil clinical criteria for FH (MEDPED criteria - PMID: 27824480)

PP1

PP1_Not Met: the variant was reported in only 1 related (1 informative meiosis) from PMID: 27824480, so PP1 is Not Met.

PM1

PM1_Not Met: variant meets PM2 but it is not located in exon 4 (located in exon 14) and is not affecting one of the highly conserved cysteins, so PM1 is not Met.

Curation History

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