NM_000527.5(LDLR):c.1056C>G (p.Cys352Trp) AND Familial hypercholesterolemia

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Nov 20, 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:: RCV000586287.3

Allele description [Variation Report for NM_000527.5(LDLR):c.1056C>G (p.Cys352Trp)]

NM_000527.5(LDLR):c.1056C>G (p.Cys352Trp)

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.1056C>G (p.Cys352Trp)

Other names:

FH Avellino-1

HGVS:

NC_000019.10:g.11110767C>G
NG_009060.1:g.26387C>G
NM_000527.5:c.1056C>GMANE SELECT
NM_001195798.2:c.1056C>G
NM_001195799.2:c.933C>G
NM_001195800.2:c.552C>G
NM_001195803.2:c.675C>G
NP_000518.1:p.Cys352Trp
NP_000518.1:p.Cys352Trp
NP_001182727.1:p.Cys352Trp
NP_001182728.1:p.Cys311Trp
NP_001182729.1:p.Cys184Trp
NP_001182732.1:p.Cys225Trp
LRG_274t1:c.1056C>G
LRG_274:g.26387C>G
LRG_274p1:p.Cys352Trp
NC_000019.9:g.11221443C>G
NM_000527.4:c.1056C>G
c.1056C>G
p.(Cys352Trp)

Protein change:

C184W

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001341; dbSNP: rs13306515

Molecular consequence:

NM_000527.5:c.1056C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1056C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.933C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.552C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.675C>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000697183	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 26, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15823280, 23375686 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV006063687	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 12, 2024)	germline	clinical testing	PubMed (18) [See all records that cite these PMIDs] 2088165, 6091915, 9974426, 10735632, 10978268, 11585102, 11810272, 11851376, 15952897, 23375686, 26723464, 27824480, 30710474, 31345425, 32977124, 34456200, 36422519, 25741868
SCV007521780	Natera, Inc.	criteria provided, single submitter (Natera Variant Classification Schema (03/2026))	Likely pathogenic (Nov 20, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9974426, 26723464 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000697183

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jul 26, 2017)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV006063687

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 12, 2024)

germline

clinical testing

PubMed (18)
[See all records that cite these PMIDs]

SCV007521780

Natera, Inc.

criteria provided, single submitter

(Natera Variant Classification Schema (03/2026))

Likely pathogenic
(Nov 20, 2024)

germline

clinical testing

PubMed (2)
[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

Effect of low-density lipoprotein receptor mutation on lipoproteins and cardiovascular disease risk: a parent-offspring study.

Koeijvoets KC, Wiegman A, Rodenburg J, Defesche JC, Kastelein JJ, Sijbrands EJ.

Atherosclerosis. 2005 May;180(1):93-9. Epub 2004 Dec 19.

PubMed [citation]

PMID:: 15823280

The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein.

Hobbs HH, Russell DW, Brown MS, Goldstein JL.

Annu Rev Genet. 1990;24:133-70. Review. No abstract available.

PubMed [citation]

PMID:: 2088165

See all PubMed Citations (19)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697183.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: The LDLR c.1056C>G (p.Cys352Trp) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. The variant of interest has not been found in a large, broad control population, ExAC in 120928 control chromosomes. This variant was reported in multiple patients with familial hypercholesterolemia (FH), including a homozygous patient whose phenotype was more severe than the heterozygous patients (Bertolini_Atherosclerosis_2013, Fouchier_HG_2001), including . A functional study suggested that the variant causes a defective LDL receptor, though the data was not provided for independent assessment (Bertolini_Atherosclerosis_2013). In addition, one clinical diagnostic laboratory classified this variant as likely 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 Color Diagnostics, LLC DBA Color Health, SCV006063687.1

#	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 replaces cysteine with tryptophan at codon 352 in the EGF-like repeat A of the LDLR protein. This variant is also known as p.Cys331Trp in the mature protein, and as FH Avellino-1 in the literature. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies in cultured fibroblasts from both heterozygous and homozygous individuals have shown that this variant causes a significant reduction in LDLR activity as well as LDL binding and internalization (PMID: 9974426, 11585102). This variant has been reported in more than 10 individuals affected with familial hypercholesterolemia (PMID: 10735632, 10978268, 11585102, 11810272, 11851376, 23375686, 27824480, 30710474, 31345425, 32977124, 34456200). This variant has also been observed in homozygous state in one individual affected with severe homozygous familial hypercholesterolemia (PMID: 9974426, 26723464, 36422519). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon: p.Cys352Tyr, p.Cys352Phe, and p.Cys352Ser, are considered to be disease-causing (ClinVar variation ID: 36450, 251619, 251617), suggesting that cysteine at this position is important for LDLR protein function. 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

From Natera, Inc., SCV007521780.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The c.1056C>G variant in LDLR is a missense variant predicted to cause substitution of cysteine to tryptophan at amino acid 352. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 9974426, 26723464). This variant is located in a functionally critical region of the protein. A different variant at the same position has been determined to be Pathogenic or Likely Pathogenic. Computational prediction algorithms indicate this variant is likely to affect gene or protein function. Given the available evidence, this variant 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

Last Updated: Apr 12, 2026

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