NM_000527.5(LDLR):c.1055G>A (p.Cys352Tyr) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Aug 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:: RCV000413322.8

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

NCBI 1000 Genomes Browser:

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000491200	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Aug 21, 2025)	germline	clinical testing	Citation Link,
SCV000925131	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Pathogenic (Nov 6, 2017)	germline	provider interpretation
SCV005625802	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	pathogenic (Apr 8, 2024)	unknown	clinical testing	PubMed (14) [See all records that cite these PMIDs] 1301956, 19026292, 30592178, 31491741, 32331935, 34037665, 28391882, 25234566, 23064986, 22698793, 21722902, 19717150, 19318025, 26467025
SCV005878113	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Apr 11, 2024)	germline	clinical testing	Citation Link

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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, provider interpretation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.

Hobbs HH, Brown MS, Goldstein JL.

Hum Mutat. 1992;1(6):445-66. Review.

PubMed [citation]

PMID:: 1301956

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

See all PubMed Citations (14)

Details of each submission

From GeneDx, SCV000491200.6

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as FH Mexico-2 and p.(C331Y); This variant is associated with the following publications: (PMID: 1301956, 19026292, 19318025, 22698793, 30592178, 32719484, 34037665, 28391882, 19717150, 29576406, 21722902, 31491741, 32331935, 23064986, 38003014, 35929461, 33533259, 25234566, Katsanis2025[preprint], 25014035, 2988123, 12459547, 38258479, 37808210)

#	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

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000925131.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	provider interpretation	not provided

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV005625802.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

The LDLR c.1055G>A (p.Cys352Tyr) variant (also known as FH Mexico-2 or C331Y) has been reported in the published literature in multiple individuals affected with familial hypercholesterolemia in heterozygous, homozygous, and compound heterozygous states (PMID: 1301956 (1992), 19026292 (2008), 19717150 (2010), 21722902 (2011), 19318025 (2009), 22698793 (2012), 23064986 (2012), 25234566 (2014), 28391882 (2017), 30592178 (2019), 31491741 (2019), 32331935 (2020)). Published family segregation data suggests that there may be incomplete penetrance with this variant (PMID: 25234566 (2014)). Assessment of experimental evidence suggests this variant results in significantly reduced LDLR activity (PMID: 1301956 (1992), 19026292 (2008)). The frequency of this variant in the general population, 0.000008 (2/250660 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV005878113.1

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

Description

The LDLR c.1055G>A; p.Cys352Tyr variant (rs193922566) is reported in the literature in numerous individuals affected with familial hypercholesterolemia (Chan 2019, Sturm 2021, Vaca 2011), including one homozygous individual with early onset presentation (Magana Torres 2014). This variant is also reported in ClinVar (Variation ID: 36450). This variant is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.98). Based on available information, this variant is considered to be pathogenic. References: Magana Torres MT et al. Homozygous familial hypercholesterolemia: the c.1055G>A mutation in the LDLR gene and clinical heterogeneity. J Clin Lipidol. 2014 Sep-Oct;8(5):525-7. PMID: 25234566. Chan ML et al. Genetic variations in familial hypercholesterolemia and cascade screening in East Asians. Mol Genet Genomic Med. 2019 Feb;7(2):e00520. PMID: 30592178. Sturm AC et al. Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis. JAMA Cardiol. 2021 Aug 1;6(8):902-909. PMID: 34037665. Vaca G et al. Mutational analysis of the LDL receptor and APOB genes in Mexican individuals with autosomal dominant hypercholesterolemia. Atherosclerosis. 2011 Oct;218(2):391-6. PMID: 21722902.

#	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 27, 2025

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