NM_000527.5(LDLR):c.691T>G (p.Cys231Gly) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Nov 21, 2025
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:: RCV001857824.8

Allele description [Variation Report for NM_000527.5(LDLR):c.691T>G (p.Cys231Gly)]

NM_000527.5(LDLR):c.691T>G (p.Cys231Gly)

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.691T>G (p.Cys231Gly)

HGVS:

NC_000019.10:g.11105597T>G
NG_009060.1:g.21217T>G
NM_000527.5:c.691T>GMANE SELECT
NM_001195798.2:c.691T>G
NM_001195799.2:c.568T>G
NM_001195800.2:c.314-1795T>G
NM_001195803.2:c.314-968T>G
NP_000518.1:p.Cys231Gly
NP_000518.1:p.Cys231Gly
NP_001182727.1:p.Cys231Gly
NP_001182728.1:p.Cys190Gly
LRG_274t1:c.691T>G
LRG_274:g.21217T>G
LRG_274p1:p.Cys231Gly
NC_000019.9:g.11216273T>G
NM_000527.4:c.691T>G
P01130:p.Cys231Gly
c.691T>G

Protein change:

C190G

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000405; UniProtKB: P01130#VAR_005342; dbSNP: rs746091400

Molecular consequence:

NM_001195800.2:c.314-1795T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-968T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.691T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.691T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.568T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia
Synonyms:: Familial hypercholesterolemias; Familial hypercholesterolaemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002149411	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 21, 2025)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 11313767, 22698793, 7548065, 7603991, 7979249, 18325082, 10422804, 10782930, 19073363, 28492532
SCV003922713	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 27, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11313767, 22698793, 33740630 Citation Link,
SCV007299278	Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service	criteria provided, single submitter (ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2020)	Pathogenic (Jul 29, 2025)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002149411

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 21, 2025)

germline

clinical testing

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

SCV003922713

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Mar 27, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV007299278

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

criteria provided, single submitter

(ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2020)

Pathogenic
(Jul 29, 2025)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
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 (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002149411.5

#	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 glycine, which is neutral and non-polar, at codon 231 of the LDLR protein (p.Cys231Gly). This variant is present in population databases (rs746091400, gnomAD 0.006%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 10422804, 11313767, 22698793). This variant is also known as C210G. ClinVar contains an entry for this variant (Variation ID: 251397). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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). This variant disrupts the p.Cys231 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 10422804, 10782930, 19073363), 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003922713.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: LDLR c.691T>G (p.Cys231Gly) results in a non-conservative amino acid change located in the fifth class A repeat (IPR002172) of the encoded protein sequence. The class A repeats form the binding sites for LDL and contain six cysteine residues involved in disulfide bond formation that are required for structural integrity (InterPro). Numerous missense changes affecting cysteine residues within LDLR class A repeats are found among patients with hypercholesterolemia (HGMD), in addition, other variants affecting the same residue (Cys231), have been reported in affected individuals (HGMD). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246490 control chromosomes (gnomAD). The variant, c.691T>G (aka. C210G), has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Heath_2001, Tichy_2012, Leren_2021), and was described as a frequent founder variant in Norwegian FH patients (Leren_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic (n=2) / likely pathogenic (n=3). Based on the evidence outlined above, the variant was 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 Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service, SCV007299278.1

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

Description

PS4,PM1,PM2,PP3

#	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		not provided	not provided	not provided	not provided

Last Updated: Apr 12, 2026

ClinVar

Relating variation to medicine