NM_000527.5(LDLR):c.1055G>A (p.Cys352Tyr) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 12, 2026
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:: RCV000722113.19

Allele description [Variation Report for NM_000527.5(LDLR):c.1055G>A (p.Cys352Tyr)]

NM_000527.5(LDLR):c.1055G>A (p.Cys352Tyr)

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.1055G>A (p.Cys352Tyr)

Other names:

NM_000527.5(LDLR):c.1055G>A

HGVS:

NC_000019.10:g.11110766G>A
NG_009060.1:g.26386G>A
NM_000527.5:c.1055G>AMANE SELECT
NM_001195798.2:c.1055G>A
NM_001195799.2:c.932G>A
NM_001195800.2:c.551G>A
NM_001195803.2:c.674G>A
NP_000518.1:p.Cys352Tyr
NP_000518.1:p.Cys352Tyr
NP_001182727.1:p.Cys352Tyr
NP_001182728.1:p.Cys311Tyr
NP_001182729.1:p.Cys184Tyr
NP_001182732.1:p.Cys225Tyr
LRG_274t1:c.1055G>A
LRG_274:g.26386G>A
LRG_274p1:p.Cys352Tyr
NC_000019.9:g.11221442G>A
NM_000527.4:c.1055G>A
P01130:p.Cys352Tyr
c.1055G>A

Protein change:

C184Y

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001339; UniProtKB: P01130#VAR_005369; dbSNP: rs193922566

Molecular consequence:

NM_000527.5:c.1055G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1055G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.932G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.551G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.674G>A - 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
SCV000052777	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 16, 2020)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 1301956, 19026292, 19318025, 21722902, 23064986, 22698793, 19717150, 25014035, 29576406, 25234566, 28391882 Citation Link,
SCV000544690	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 7, 2026)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 1301956, 19717150, 21722902, 22698793, 23064986, 25234566, 28492532
SCV000909469	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 1, 2025)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 1301956, 2088165, 6091915, 15952897, 21722902, 22698793, 23064986, 25234566, 32331935, 33533259, 34037665, 35929461, 25741868
SCV007521778	Natera, Inc.	criteria provided, single submitter (Natera Variant Classification Schema (03/2026))	Pathogenic (Jan 12, 2026)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19717150, 21722902, 23064986, 22698793, 34029164 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

Longitudinal evaluation and assessment of cardiovascular disease in patients with homozygous familial hypercholesterolemia.

Kolansky DM, Cuchel M, Clark BJ, Paridon S, McCrindle BW, Wiegers SE, Araujo L, Vohra Y, Defesche JC, Wilson JM, Rader DJ.

Am J Cardiol. 2008 Dec 1;102(11):1438-43. doi: 10.1016/j.amjcard.2008.07.035. Epub 2008 Sep 11.

PubMed [citation]

PMID:: 19026292

Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform.

Alonso R, Defesche JC, Tejedor D, Castillo S, Stef M, Mata N, Gomez-Enterria P, Martinez-Faedo C, Forga L, Mata P.

Clin Biochem. 2009 Jun;42(9):899-903. doi: 10.1016/j.clinbiochem.2009.01.017. Epub 2009 Feb 6.

PubMed [citation]

PMID:: 19318025

See all PubMed Citations (21)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000052777.3

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

Description

Variant summary: LDLR c.1055G>A (p.Cys352Tyr) results in a non-conservative amino acid change located in the EGF-like domain and EGF-like calcium-binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several variants at the same codon have been associated with Familial Hypercholesterolemia (C352R, C352F, C352S, C352W), as well as the immediately adjacent codons, suggesting the locus is important for gene function.The variant allele was found at a frequency of 8e-06 in 250860 control chromosomes. c.1055G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (example, Hobbs_1992, Kolansky_2008, Ahmad_2012, Vaca_2011, Magana Torres_2014, Tichy_2012, Alonso_2009, Junyent_2010, Mabuchi_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal LDL receptor activity (Kolansky_2008). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic (n=6). 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000544690.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 352 of the LDLR protein (p.Cys352Tyr). This variant is present in population databases (rs193922566, gnomAD 0.006%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 1301956, 19717150, 21722902, 22698793, 23064986, 25234566). It has also been observed to segregate with disease in related individuals. 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. This variant is also known as p.Cys331Tyr. ClinVar contains an entry for this variant (Variation ID: 36450). 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%. 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, SCV000909469.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

This missense variant replaces cysteine with tyrosine at codon 352 in the EGF-like repeat A of the LDLR protein. This variant is also known as p.Cys331Tyr in the mature 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. An experimental study has shown that this variant results in a significantly reduced LDLR activity in cells from a patient compound heterozygous for this variant and p.Cys364Arg (PMID: 1301956). This variant has been reported in more than ten individuals affected with familial hypercholesterolemia (PMID: 1301956, 21722902, 22698793, 23064986, 32331935, 33533259, 34037665, 35929461Color internal data). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in an individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 1301956), as well as in homozygous state (PMID: 25234566). It has been shown that this variant segregates with disease in multiple affected individuals in one family (PMID: 25234566). This variant has been identified in 2/250660 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon: p.Cys352Phe, p.Cys352Trp, and p.Cys352Ser, are considered to be disease-causing (ClinVar variation ID: 251619, 251622, 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., SCV007521778.1

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

Description

The c.1055G>A variant in LDLR is a missense variant predicted to cause substitution of cysteine to tyrosine at amino acid 352. This variant has been observed in affected individual(s) with monoallelic occurrence (heterozygous/hemizygous) (PMID: 19717150, 21722902, 23064986, 22698793). Functional studies show that this variant may disrupt protein function (PMID: 34029164). 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 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: Aug 4, 2026

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