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.2441G>A (p.Arg814Gln)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA023671

161278 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 76f43246-b267-4a3d-a188-606fc6f02000

Approved on: 2024-08-30

Published on: 2024-10-09

HGVS expressions

NM_000527.5:c.2441G>A

NM_000527.5(LDLR):c.2441G>A (p.Arg814Gln)

NC_000019.10:g.11129564G>A

CM000681.2:g.11129564G>A

NC_000019.9:g.11240240G>A

CM000681.1:g.11240240G>A

NC_000019.8:g.11101240G>A

NG_009060.1:g.45184G>A

ENST00000252444.10:c.2699G>A

ENST00000559340.2:c.*510G>A

ENST00000560467.2:c.2321G>A

ENST00000558518.6:c.2441G>A

ENST00000252444.9:c.2695G>A

ENST00000455727.6:c.1937G>A

ENST00000535915.5:c.2318G>A

ENST00000545707.5:c.1907G>A

ENST00000557933.5:c.2503G>A

ENST00000558013.5:c.2441G>A

ENST00000558518.5:c.2441G>A

ENST00000560628.1:n.108+1910G>A

NM_000527.4:c.2441G>A

NM_001195798.1:c.2441G>A

NM_001195799.1:c.2318G>A

NM_001195800.1:c.1937G>A

NM_001195803.1:c.1907G>A

NM_001195798.2:c.2441G>A

NM_001195799.2:c.2318G>A

NM_001195800.2:c.1937G>A

NM_001195803.2:c.1907G>A

Uncertain Significance

BS1 PS3 PP3

PM6 PM2 PM3 PM1 PM4 PM5 BA1 BS2 BS4 BS3 BP5 BP7 BP2 BP3 BP4 BP1 PVS1 PS2 PS4 PS1 PP1 PP4 PP2

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.2441G>A (p.Arg814Gln) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes BS1, PS3 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 30 August 2024. The supporting evidence is as follows: BS1: FAF=0.003604 (0.3604%) in African/African American exomes + genomes (gnomAD v4.1.0). PP3: REVEL=0.768. PS3: Level 1 assay, PMID 37739193 (Mori et al., 2024): Heterologous cells (HepG2 transfected cells with CRISPR/Cas9), FACS, WB, and CLSM assays. FACS: ~40% cell surface LDLR, 6% binding, and 7% uptake; WB: altered expression of LDLR in HepG2 cells transfected ---- results are below 70% of wild-type, consistent with damaging effect.

BS1

FAF=0.003604 (0.3604%) in African/African American exomes + genomes (gnomAD v4.1.0). It is above 0.2%, so met

PS3

PS3 - Level 1 assay: PMID 37739193: Heterologous cells (HepG2 transfected cells with CRISPR/Cas9), FACS, WB, and CLSM assays - results - FACS: ~40% cell surface LDLR, 6% binding, and 7% uptake; WB: altered expression of LDLR in HepG2 cells transfected ---- results are below 70% of wild-type, so functional study is consistent with damaging effect;

PP3

PP3 - REVEL=0.768.

PM6

no de novo occurrence

PM2

PopMax MAF=0.003976 (0.3976%) in African/African American exomes + genomes (gnomAD v4.1.0). It is not below 0.2%, so not met

PM3

Variant does not meet PM2. It has been identified in two index cases with homozygous FH phenotype and LDLR c.1072T>C or c.682del from PMID 27784735 and Centre de Génétique Moléculaire et Chromosomique, respectively. Also, these variants are suspected to be in trans, so not met

PM1

Variant located in exon 17 (not in exon 4) and not in one of 60 highly conserved cysteine residues, and PM2 is not met.

PM4

missense, not applicable

PM5

Another missense variant at the same codon that predicts a different amino acid change [p.(Arg814Trp)], but not classified as pathogenic, so not met

BA1

FAF=0.003604 (0.3604%) in African/African American exomes + genomes (gnomAD v4.1.0). It is not above 0.5%, so not met

BS2

not identified in normolipidemic individuals

BS4

Only 1 relative with FH phenotype without the variant from one family from Centre de Génétique Moléculaire et Chromosomique, France - evidence is not enough

BS3

PMID 25647241 - In vitro microscopy assays in HeLa cells - LDLR activity is equal to WT - likely neutral. Only part of the cycle studied, so not met

BP5

not applicable

BP7

missense, not applicable

BP2

Variant identified in three index cases with heterozygous FH phenotype and LDLR variants c.1056-1060+3del; c.2389G>A or duplication of exons 13-14, classified as pathogenic by these guidelines, from Centre de Génétique Moléculaire et Chromosomique. But as these variants are "suspected to be in trans" but not confirmed in trans, BP2 is not applied

BP3

not applicable

BP4

PP3 - REVEL=0.768.

BP1

not applicable

PVS1

missense but not in the first codon, not applicable

PS2

no de novo occurrence

PS4

Variant is identified in at least 10 unrelated index cases (1 case with Simon Broome criteria of possible FH from Genomics Medicine Unit, Navarrabiomed - idiSNA, Spain; 7 cases with DLCN score >=6 and 5 cases with Simon Broome criteria of possible FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, France). Variant does not meet PM2, so PS4 is not met.

PS1

no other missense variants that lead to the same amino acid change in the same codon, so not met

PP1

no evidence of segregation

PP4

PP2

not applicable

Curation History

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