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.1897C>T (p.Arg633Cys)

CA10576325

226379 (ClinVar)

Gene: LDLR (HGNC:3949)

Condition: hypercholesterolemia, familial (MONDO:0007750)

Inheritance Mode: Semidominant inheritance

UUID: ca9c3746-51fc-4695-995a-81bed008f106

Approved on: 2023-11-07

Published on: 2025-08-26

HGVS expressions

NM_000527.5:c.1897C>T

NM_000527.5(LDLR):c.1897C>T (p.Arg633Cys)

NC_000019.10:g.11120143C>T

CM000681.2:g.11120143C>T

NC_000019.9:g.11230819C>T

CM000681.1:g.11230819C>T

NC_000019.8:g.11091819C>T

NG_009060.1:g.35763C>T

ENST00000252444.10:c.2155C>T

ENST00000559340.2:c.1757C>T

ENST00000560467.2:c.1777C>T

ENST00000558518.6:c.1897C>T

ENST00000252444.9:c.2151C>T

ENST00000455727.6:c.1393C>T

ENST00000535915.5:c.1774C>T

ENST00000545707.5:c.1516C>T

ENST00000557933.5:c.1897C>T

ENST00000558013.5:c.1897C>T

ENST00000558518.5:c.1897C>T

ENST00000559340.1:c.478C>T

NM_000527.4:c.1897C>T

NM_001195798.1:c.1897C>T

NM_001195799.1:c.1774C>T

NM_001195800.1:c.1393C>T

NM_001195803.1:c.1516C>T

NM_001195798.2:c.1897C>T

NM_001195799.2:c.1774C>T

NM_001195800.2:c.1393C>T

NM_001195803.2:c.1516C>T

Pathogenic

PM5 PM2 PS4 PP4 PP1 PP3

PM3 PM1 PM4 PM6 BA1 BS2 BS4 BS3 BS1 BP7 BP2 BP4 PVS1 PS2 PS3 PS1

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.1897C>T (p.Arg633Cys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PM2, PM5, PP1, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00003 (0.003%) in South Asian exomes (gnomAD version 2.1.1). PP3: REVEL= 0.845. PM5: There is 1 variant in the same codon classified as Pathogenic by these guidelines, NM_000527.5(LDLR):c.1898G>A (p.Arg633His) (ClinVar ID: 226380). PS4, PP4: Variant meets PM2 and is identified in at least 10 unrelated index cases who fulfill criteria for FH (Simon-Broome criteria or with DLCN score >=6) from different labs (Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory, US; Robarts Research Institute, Canada; Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Czech Republic; Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal; Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; PMID 17094996 (Tosi et al., 2007), UK; PMID 31491741 (Hori et al., 2019), Japan) after alternative causes of high cholesterol were excluded. PP1: Variant segregates with phenotype in at least 2 informative meiosis in 2 families from different labs (Cardiovascular Research Group, Instituto Nacional de Saúde Doutor Ricardo Jorge, Portugal; Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France): 2 affected family members have the variant.

PM5

Variant NM_000527.5(LDLR):c.1898G>A (p.Arg633His) (ClinVar 226380) is classified as pathogenic by these guidelines.

PM2

PopMax MAF = 0.00003 (0.003%) in South Asian exomes (gnomAD version 2.1.1).

PS4

Variant meets PM2 and is identified in at least 10 unrelated index cases who fulfill SB possible or DLCN>=6 criteria for FH from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory, Robarts Research Institute and Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, PMID 17094996, PMID 31491741, PMID after alternative causes of high cholesterol were excluded.

PP4

Variant meets PM2 and is identified in at least 1 index case who fulfills SB possible or DLCN>=6 criteria for FH from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory, Robarts Research Institute and Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, after alternative causes of high cholesterol were excluded.

PP1

Variant segregates with FH phenotype in at least 2 informative meiosis from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge and Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies.

PP3

REVEL= 0.845. This is greater than 0.75 so PP3 is met.

PM3

Not met.

PM1

Not located in exon 4 or at a cysteine residue.

PM4

Not an in-frame deletion or insertion.

PM6

Not met.

BA1

FAF = 0.000002920 (0.0002920%) in European (non-Finnish) exomes (gnomAD version 2.1.1).

BS2

No data available.

BS4

Not met.

BS3

Not met.

BS1

FAF = 0.000002920 (0.0002920%) in European (non-Finnish) exomes (gnomAD version 2.1.1).

BP7

Not a synonymous variant.

BP2

No data available.

BP4

REVEL= 0.845. This is greater than 0.5 so BP4 is not met.

PVS1

Not a null variant.

PS2

Not met.

PS3

Level 3 assay: PMID 32015373. LDLR expression, binding or internalization not <70% of wild-type. Heterozygous patient cells (CHO), FACS/ Microscopy assays - result - 70% cell surface LDLR, 72% LDL-LDLR binding and 75% uptake.

PS1

No other pathogenic variants at the same codon that lead to the same amino acid change.

Curation History

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