NM_000527.5(LDLR):c.589T>G (p.Cys197Gly) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 19, 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:: RCV000775044.9

Allele description [Variation Report for NM_000527.5(LDLR):c.589T>G (p.Cys197Gly)]

NM_000527.5(LDLR):c.589T>G (p.Cys197Gly)

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.589T>G (p.Cys197Gly)

HGVS:

NC_000019.10:g.11105495T>G
NG_009060.1:g.21115T>G
NM_000527.5:c.589T>GMANE SELECT
NM_001195798.2:c.589T>G
NM_001195799.2:c.466T>G
NM_001195800.2:c.314-1897T>G
NM_001195803.2:c.314-1070T>G
NP_000518.1:p.Cys197Gly
NP_000518.1:p.Cys197Gly
NP_001182727.1:p.Cys197Gly
NP_001182728.1:p.Cys156Gly
LRG_274t1:c.589T>G
LRG_274:g.21115T>G
LRG_274p1:p.Cys197Gly
NC_000019.9:g.11216171T>G
NM_000527.4:c.589T>G
c.589T>G

Protein change:

C156G

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001765; dbSNP: rs730882085

Molecular consequence:

NM_001195800.2:c.314-1897T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1070T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.589T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.589T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.466T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia
Synonyms:: Familial hypercholesterolaemia
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
SCV000830690	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 11, 2025)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 7548065, 7603991, 7979249, 18325082, 1301956, 18096825, 20145306, 20538126, 20809525, 21276076, 23064986, 24014831, 27765764, 27816806, 28492532
SCV000909141	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 19, 2025)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 15952897, 20809525, 24014831, 28964736, 32143996, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000830690

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 11, 2025)

germline

clinical testing

PubMed (15)
[See all records that cite these PMIDs]

SCV000909141

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 19, 2025)

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	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 (19)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000830690.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (15)

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 197 of the LDLR protein (p.Cys197Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 20809525, 24014831). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 377,766 individuals referred to our laboratory for LDLR testing. ClinVar contains an entry for this variant (Variation ID: 251308). 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.Cys197 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 1301956, 18096825, 20145306, 20538126, 20809525, 21276076, 23064986, 24014831, 27765764, 27816806), 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, SCV000909141.2

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

Description

This missense variant replaces cysteine with glycine at codon 197 in the fifth LDLR type A repeat of the ligand binding domain of the LDLR protein. This variant is also known as p.Cys176Gly in the mature protein. 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. A functional study has shown that this variant results in the loss of LDLR activity (PMID: 24014831). This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 20809525, 24014831, 28964736, 32143996). One of these individuals was compound heterozygous for this variant and deletion of exons 4-18 and was affected with severe familial hypercholesterolemia (PMID: 24014831). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants occurring at the same amino acid position (p.Cys197Arg, p.Cys197Phe and p.Cys197Tyr) are known to cause disease deleterious (ClinVar), indicating the functional and clinical importance of this position. 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: Feb 23, 2026

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