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

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 9, 2023
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:: RCV002372212.3

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]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002624552	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Mar 9, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10735632, 11462246, 12730724, 23375686, 25921077 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002624552

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Mar 9, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	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

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 (5)

Details of each submission

From Ambry Genetics, SCV002624552.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The p.C134R pathogenic mutation (also known as c.400T>C), located in coding exon 4 of the LDLR gene, results from a T to C substitution at nucleotide position 400. The cysteine at codon 134 is replaced by arginine, an amino acid with highly dissimilar properties. This variant has been described in patients with familial hypercholesterolemia (FH) from various ethnic groups (Lombardi MP et al. Clin Genet. 2000;57:116-24; Nauck MS et al. Hum Mutat. 2001;18:165-6; El Messal M et al. J Hum Genet. 2003;48:199-203; Han Y et al. Int J Pediatr Otorhinolaryngol. 2015;79:1148-51). Other alterations involving the same amino acid, p.C134F (c.401G>T), p.C134W (c.402C>G), and p.C134Y (c.401G>A), have also been reported in FH cohorts (Bertolini S et al. Atherosclerosis. 2013;227(2):342-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 3 (Ambry internal data). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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

Last Updated: Oct 20, 2024

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