NM_000527.5(LDLR):c.400T>C (p.Cys134Arg) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Mar 9, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000211566.12

Allele description [Variation Report for NM_000527.5(LDLR):c.400T>C (p.Cys134Arg)]

NM_000527.5(LDLR):c.400T>C (p.Cys134Arg)

Gene:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.5(LDLR):c.400T>C (p.Cys134Arg)

HGVS:

NC_000019.10:g.11105306T>C
NG_009060.1:g.20926T>C
NM_000527.5:c.400T>CMANE SELECT
NM_001195798.2:c.400T>C
NM_001195799.2:c.277T>C
NM_001195800.2:c.314-2086T>C
NM_001195803.2:c.314-1259T>C
NP_000518.1:p.Cys134Arg
NP_000518.1:p.Cys134Arg
NP_001182727.1:p.Cys134Arg
NP_001182728.1:p.Cys93Arg
LRG_274t1:c.400T>C
LRG_274:g.20926T>C
LRG_274p1:p.Cys134Arg
NC_000019.9:g.11215982T>C
NM_000527.4:c.400T>C
c.400T>C

Protein change:

C134R

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000329; dbSNP: rs875989900

NCBI 1000 Genomes Browser:

rs875989900

Molecular consequence:

NM_001195800.2:c.314-2086T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1259T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.400T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.400T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.277T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hypercholesterolemia, familial, 1
Synonyms:: LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000268561	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	no assertion criteria provided	Pathogenic (Mar 24, 2016)	germline	clinical testing
SCV000294685	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 10735632, 11462246, 12730724 Citation Link,
SCV000606104	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV004820162	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 9, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 10735632, 11462246, 12417285, 12730724, 15256764, 15952897, 25921077, 29233637, 32143996, 32759540, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing, research
not provided	germline	yes	4	not provided	not provided	3	not provided	clinical testing, literature only

Citations

PubMed

Molecular genetic testing for familial hypercholesterolemia: spectrum of LDL receptor gene mutations in The Netherlands.

Lombardi MP, Redeker EJ, Defesche JC, Kamerling SW, Trip MD, Mannens MM, Havekes LM, Kastelein JJ.

Clin Genet. 2000 Feb;57(2):116-24.

PubMed [citation]

PMID:: 10735632

Identification of recurrent and novel mutations in the LDL receptor gene in German patients with familial hypercholesterolemia.

Nauck MS, Köster W, Dörfer K, Eckes J, Scharnagl H, Gierens H, Nissen H, Nauck MA, Wieland H, März W.

Hum Mutat. 2001 Aug;18(2):165-6.

PubMed [citation]

PMID:: 11462246

See all PubMed Citations (11)

Details of each submission

From Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268561.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From LDLR-LOVD, British Heart Foundation, SCV000294685.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (3)
2	not provided	1	not provided	not provided	literature only	PubMed (3)
3	not provided	1	not provided	not provided	literature only	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
2	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
3	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606104.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004820162.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (11)

Description

This missense variant replaces cysteine with arginine at codon 134 in the third LDLR type A repeat of the ligand binding domain of the LDLR protein. This variant is also known as p.Cys113Arg in the mature protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been reported, this variant changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the ligand binding domain (PMID: 15952897) and is expected to have deleterious impact on the LDLR protein folding and stability. This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 10735632, 11462246, 12417285, 12730724, 15256764, 25921077, 29233637, 32143996, 32759540). It has also been observed to segregate with high LDL-C levels and xanthomas in three related individuals (PMID: 25921077). This variant has been identified in 1/251176 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Jun 22, 2025

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