NM_000527.5(LDLR):c.400T>C (p.Cys134Arg) AND Homozygous familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 15, 2017
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000844756.4

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:: Homozygous familial hypercholesterolemia
Synonyms:: Familial hypercholesterolemia - homozygous
Identifiers:: MONDO: MONDO:0018328; MedGen: C0342881

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000711781	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Aug 15, 2017)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10735632, 12730724, 25921077, 11462246, 28349240, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000711781

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Aug 15, 2017)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	7	7	not provided	not provided	not provided	clinical testing

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

Familial hypercholesterolemia in Morocco: first report of mutations in the LDL receptor gene.

El Messal M, Aït Chihab K, Chater R, Vallvé JC, Bennis F, Hafidi A, Ribalta J, Varret M, Loutfi M, Rabès JP, Kettani A, Boileau C, Masana L, Adlouni A.

J Hum Genet. 2003;48(4):199-203. Epub 2003 Mar 18.

PubMed [citation]

PMID:: 12730724

See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000711781.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	PubMed (6)

Description

The p.Cys134Arg (previously p.Cys113Arg) variant in LDLR has been reported in >4 individuals with familial hypercholesterolemia (FH) and segregated with disease with 2 affected relatives from 1 family (Lombardi 2000, Nauck 2001, El Messal 2 003, Han 2015, ClinVar: Variation ID 226322). It has also been identified in 1/1 11580 European chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org/; dbSNP rs875989900). Computational prediction tools and conservation analysis suggest that the p.Cys134Arg variant may impact the prote in. Additionally, other missense variants at this position (p.Cys134Tyr, p.Cys13 4Phe, p.Cys134Gly and p.Cys134Trp) have been reported in individuals with famili al hypercholesterolemia (Human Gene Mutation Database: Stenson et al., 2017), In summary, although additional studies are required to fully establish its clinic al significance, the p.Cys134Arg variant is likely pathogenic for autosomal domi nant FH. ACMG/AMP criteria applied: PS4_Moderate, PM2, PM5_Supporting, PP3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		7	not provided	7	not provided

Last Updated: Jul 13, 2025

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