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

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 10, 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:: RCV000775036.10

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:: Familial hypercholesterolemia (FH)
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000752410	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 10, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 10735632, 12730724, 25921077, 7548065, 7603991, 7979249, 18325082, 11462246, 23375686, 28492532
SCV000909133	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 24, 2022)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 10735632, 11462246, 12417285, 12730724, 15256764, 15952897, 25921077, 29233637, 32143996, 32759540, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000752410

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 10, 2023)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV000909133

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 24, 2022)

germline

clinical testing

PubMed (11)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Disulfide bridges of a cysteine-rich repeat of the LDL receptor ligand-binding domain.

Bieri S, Djordjevic JT, Daly NL, Smith R, Kroon PA.

Biochemistry. 1995 Oct 10;34(40):13059-65.

PubMed [citation]

PMID:: 7548065

Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor.

Daly NL, Scanlon MJ, Djordjevic JT, Kroon PA, Smith R.

Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6334-8.

PubMed [citation]

PMID:: 7603991
PMCID:: PMC41512

See all PubMed Citations (17)

Details of each submission

From Invitae, SCV000752410.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 134 of the LDLR protein (p.Cys134Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 10735632, 11462246, 12730724, 25921077). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys113Arg. ClinVar contains an entry for this variant (Variation ID: 226322). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). This variant disrupts the p.Cys134 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11462246, 23375686), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000909133.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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. Different missense variants occurring at the same codon (p.Cys134Tyr, p.Cys134Phe, p.Cys134Trp) are known to be disease-causing (ClinVar variation ID: 251203, 251204, 251205). This p.Cys134Arg 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 7, 2024

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