NM_000527.5(LDLR):c.81C>G (p.Cys27Trp) AND Familial hypercholesterolemia

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 29, 2024
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:: RCV000588365.10

Allele description

NM_000527.5(LDLR):c.81C>G (p.Cys27Trp)

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.81C>G (p.Cys27Trp)

Other names:

NP_000518.1:p.C27W; NM_000527.5(LDLR):c.81C>G

HGVS:

NC_000019.10:g.11100236C>G
NG_009060.1:g.15856C>G
NM_000527.5:c.81C>GMANE SELECT
NM_001195798.2:c.81C>G
NM_001195799.2:c.81C>G
NM_001195800.2:c.81C>G
NM_001195803.2:c.81C>G
NP_000518.1:p.Cys27Trp
NP_000518.1:p.Cys27Trp
NP_001182727.1:p.Cys27Trp
NP_001182728.1:p.Cys27Trp
NP_001182729.1:p.Cys27Trp
NP_001182732.1:p.Cys27Trp
LRG_274t1:c.81C>G
LRG_274:g.15856C>G
LRG_274p1:p.Cys27Trp
NC_000019.9:g.11210912C>G
NM_000527.4(LDLR):c.81C>G
NM_000527.4:c.81C>G
P01130:p.Cys27Trp
c.81C>G
p.(Cys27Trp)

Protein change:

C27W

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000352; UniProtKB: P01130#VAR_005304

Molecular consequence:

NM_000527.5:c.81C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.81C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.81C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.81C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.81C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia
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
SCV000697253	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 12, 2017)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25463123, 19026292, 23375686, 9259195, 1301956 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV001225810	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 11668627, 14974088, 19026292, 25463123, 27497240, 27824480, 7548065, 7603991, 7979249, 18325082, 28492532
SCV001434982	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 2, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001734617	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 29, 2023)	germline	clinical testing	PubMed (18) [See all records that cite these PMIDs] 1301956, 2088165, 6091915, 9259195, 11317361, 11668627, 14974088, 15952897, 16250003, 19026292, 23375686, 25463123, 27497240, 27824480, 31345425, 33807407, 34297352, 25741868

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 (23)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697253.1

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

Description

Variant summary: The LDLR c.81C>G (p.Cys27Trp) variant (alternatively also known as C6W and FH San Francisco) substitutes a Cys residue located in LDL receptor class A repeat which forms ligand binding domain (InterPro, Klancar_2015, Bertolini_2013, Hobbs_1992). The ligand-binding domain contains seven or eight 40-amino acid LDLR class A (cysteine-rich) repeats, each of which contains a coordinated calcium ion and six cysteine residues involved in disulphide bond formation (InterPro, PMID: 6091915). Therefore, this variant is predicted to be deleterious for protein function as it breaks down one of the disulphide bonds. 5/5 in silico tools also predict damaging outcome for this variant. This variant was found in 2/121358 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). In literature, this variant is widely reported as a pathogenic variant found mainly in FH patients of European origin (Klancar_2015, Mollaki_2014,Kolansky_2008, Bertolini_2013, Day_1997, Hobbs_1992). Genotype-phenotype correlation study showed that this variant causes a milder disease (Mollaki_2014). A functional study showed that this variant leads to impaired LDL receptor activity (Hobbs_1992). Multiple reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, 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

From Invitae, SCV001225810.5

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

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 27 of the LDLR protein (p.Cys27Trp). This variant is present in population databases (rs2228671, gnomAD 0.004%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 11668627, 14974088, 19026292, 25463123, 27497240, 27824480). This variant is also known as C6W. ClinVar contains an entry for this variant (Variation ID: 226304). 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 with a positive predictive value of 95%. 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). 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 Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV001434982.1

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

Description

This c.81C>G (p.Cys27Trp) variant in the LDLR gene has been reported in multiple unrelated individuals with familial hypercholesterolemia (PMID: 1301956, 9259195, 11317361, 11668627, 16250003, 23375686) and is extremely rare in the general population. Functional studies have reported that the mutant LDLR protein retains 15-30% of receptor activity compared with wildtype LDLR protein (PMID: 1301956). Therefore, this c.81C>G (p.Cys27Trp) variant in the LDLR gene is classified as likely 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, SCV001734617.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (18)

Description

This missense variant (also known as p.Cys6Trp in the mature protein) replaces cysteine with tryptophan at codon 27 in the LDLR type A repeat 1 of the LDLR protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study performed with cells from an individual affected with homozygous familial hypercholesterolemia has indicated that the mutant protein retains 15-30% of receptor activity compared with the wild type LDLR protein (PMID: 1301956). This variant has been observed in over 60 individuals affected with familial hypercholesterolemia (PMID: 1301956, 9259195, 11317361, 11668627, 14974088, 16250003, 23375686, 25463123, 27497240, 27824480, 31345425, 33807407, 34297352). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia, indicating that this variant contributes to disease (PMID: 19026292, 23375686). This variant has been identified in 4/250746 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the 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: Sep 1, 2024

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