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.1796T>C (p.Leu599Ser)

CA10585616

252035 (ClinVar)

Gene: LDLR (HGNC:3949)

Condition: hypercholesterolemia, familial (MONDO:0007750)

Inheritance Mode: Semidominant inheritance

UUID: 2b248b47-0882-4bbf-ad0b-7a7d02443545

Approved on: 2022-07-22

Published on: 2025-09-16

HGVS expressions

NM_000527.5:c.1796T>C

NM_000527.5(LDLR):c.1796T>C (p.Leu599Ser)

NC_000019.10:g.11116949T>C

CM000681.2:g.11116949T>C

NC_000019.9:g.11227625T>C

CM000681.1:g.11227625T>C

NC_000019.8:g.11088625T>C

NG_009060.1:g.32569T>C

ENST00000252444.10:c.2054T>C

ENST00000559340.2:c.1705+737T>C

ENST00000560467.2:c.1676T>C

ENST00000558518.6:c.1796T>C

ENST00000252444.9:c.2050T>C

ENST00000455727.6:c.1292T>C

ENST00000535915.5:c.1673T>C

ENST00000545707.5:c.1415T>C

ENST00000557933.5:c.1796T>C

ENST00000558013.5:c.1796T>C

ENST00000558518.5:c.1796T>C

ENST00000559340.1:c.426+737T>C

NM_000527.4:c.1796T>C

NM_001195798.1:c.1796T>C

NM_001195799.1:c.1673T>C

NM_001195800.1:c.1292T>C

NM_001195803.1:c.1415T>C

NM_001195798.2:c.1796T>C

NM_001195799.2:c.1673T>C

NM_001195800.2:c.1292T>C

NM_001195803.2:c.1415T>C

Likely Pathogenic

PM2 PS4_Moderate PP4 PP3

PM5 PS3 PP1

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.1796T>C (p.Leu599Ser) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PS4_Moderate, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 22 July 2022. The supporting evidence is as follows: PM2: Variant is absent from gnomAD v2.1.1. PP3: REVEL = 0.779. PS4, PP4: Variant meets PM2 and is identified in 9 unrelated index cases fulfilling FH clinical criteria (5 cases with DLCN score ≥6 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; 1 meeting Simon Broome criteria from PMID 12436241 (Amsellem et al., 2002), APHP Saint Antoine Hospital, Paris, France; 1 meeting Simon Broome criteria from PMID 17094996 (Tosi et al., 2007), UK; 1 with DLCN score ≥6 from PMID 19318025 (Alonso et al., 2009), Spain; and 1 with DLCN score ≥6 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, France).

PM2

Variant is absent from gnomAD v2.1.1

PS4_Moderate

PS4: Variant meets PM2 and is identified in 9 unrelated index cases fulfilling FH clinical criteria (5 with DLCN > 6 from Centre de Génétique Moléculaire et Chromosomique, 1 fullfilling SB clinical criteria for FH from PMID 12436241, 1 fullfilling SB clinical criteria for FH from PMID 17094996, 1 with DLCN>6 from PMID 19318025, and 1 with DLCN>6 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon

PP4

Variant meets PM2 and is identified in at least 5 index case who fulfills criteria for FH from Centre de Génétique Moléculaire et Chromosomique, after alternative causes of high cholesterol were excluded.

PP3

REVEL = 0.779. It is above 0.75, so PP3 is met.

PM5

1 other missense variants in the same codon: - NM_000527.5(LDLR):c.1796T>G (p.Leu599Trp) (ClinVar ID 252036) - Uncertain significance by these guidelines There are no variants in the same codon classified as Pathogenic by these guidelines.

PS3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Curation History

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