NM_000527.5(LDLR):c.1130G>A (p.Cys377Tyr) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 24, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003736671.1

Allele description [Variation Report for NM_000527.5(LDLR):c.1130G>A (p.Cys377Tyr)]

NM_000527.5(LDLR):c.1130G>A (p.Cys377Tyr)

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.1130G>A (p.Cys377Tyr)

HGVS:

NC_000019.10:g.11111583G>A
NG_009060.1:g.27203G>A
NM_000527.5:c.1130G>AMANE SELECT
NM_001195798.2:c.1130G>A
NM_001195799.2:c.1007G>A
NM_001195800.2:c.626G>A
NM_001195803.2:c.749G>A
NP_000518.1:p.Cys377Tyr
NP_000518.1:p.Cys377Tyr
NP_001182727.1:p.Cys377Tyr
NP_001182728.1:p.Cys336Tyr
NP_001182729.1:p.Cys209Tyr
NP_001182732.1:p.Cys250Tyr
LRG_274t1:c.1130G>A
LRG_274:g.27203G>A
LRG_274p1:p.Cys377Tyr
NC_000019.9:g.11222259G>A
NM_000527.4:c.1130G>A
c.1130G>A

Protein change:

C209Y

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000529; dbSNP: rs879254801

NCBI 1000 Genomes Browser:

rs879254801

Molecular consequence:

NM_000527.5:c.1130G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1130G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1007G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.626G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.749G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004564520	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Apr 24, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004564520

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)

Pathogenic
(Apr 24, 2023)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004564520.1

#	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.1130G>A; p.Cys377Tyr variant (rs879254801), also known as Cys356Tyr in legacy nomenclature, is reported in the literature in the heterozygous and compound heterozygous states in numerous individuals affected with familial hypercholesterolemia (Ekstrom 1998, Benedek 2021, Gabcova 2017, Marco-Benedi 2022, Rieck 2020, Wang 2018). This variant is also reported in ClinVar (Variation ID: 251681) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other amino acid substitutions at this codon (Arg, Gly, Phe, Ser) have been reported in individuals with familial hypercholesterolemia and are considered to be disease causing (Bertolini 2020, Bertolini 2013, Gabcova 2017, Wu 2014). Computational analyses predict that this variant is deleterious (REVEL: 0.984). Based on the available information, this variant is considered to be pathogenic. References: Ekstrom U et al. Mutations in the low-density lipoprotein receptor gene in Swedish familial hypercholesterolaemia patients: clinical expression and treatment response. Eur J Clin Invest. 1998 Sep;28(9):740-7. PMID: 9767373. Benedek P et al. Founder effects facilitate the use of a genotyping-based approach to molecular diagnosis in Swedish patients with familial hypercholesterolaemia. J Intern Med. 2021 Aug;290(2):404-415. PMID: 33955087. Bertolini S et al. Italian Study Group of Homozygous Familial Hypercholesterolemia. Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features. Atherosclerosis. 2020 Nov;312:72-78. PMID: 32977124. Bertolini S et al. Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. Atherosclerosis. 2013 Apr;227(2):342-8. PMID: 23375686. Gabcova D et al. The molecular genetic background of familial hypercholesterolemia: data from the Slovak nation-wide survey. Physiol Res. 2017 Mar 31;66(1):75-84. PMID: 27824480. Marco-Benedi V et al. Lipoprotein(a) in hereditary hypercholesterolemia: Influence of the genetic cause, defective gene and type of mutation. Atherosclerosis. 2022 May;349:211-218. PMID: 34456049. Rieck L et al. Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia. Clin Genet. 2020 Nov;98(5):457-467. PMID: 32770674. Wang F et al. Genetic analysis in a compound heterozygote family with familial hypercholesterolemia. Mol Med Rep. 2018 Jun;17(6):8439-8449. PMID: 29693183. Wu WF et al. Use of targeted exome sequencing in genetic diagnosis of Chinese familial hypercholesterolemia. PLoS One. 2014 Apr 10;9(4):e94697. PMID: 24722143.

#	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 25, 2025

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