NM_000527.5(LDLR):c.362G>A (p.Cys121Tyr) AND Cardiovascular phenotype

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 14, 2020
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:: RCV002453273.2

Allele description [Variation Report for NM_000527.5(LDLR):c.362G>A (p.Cys121Tyr)]

NM_000527.5(LDLR):c.362G>A (p.Cys121Tyr)

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.362G>A (p.Cys121Tyr)

HGVS:

NC_000019.10:g.11105268G>A
NG_009060.1:g.20888G>A
NM_000527.5:c.362G>AMANE SELECT
NM_001195798.2:c.362G>A
NM_001195799.2:c.239G>A
NM_001195800.2:c.314-2124G>A
NM_001195803.2:c.314-1297G>A
NP_000518.1:p.Cys121Tyr
NP_000518.1:p.Cys121Tyr
NP_001182727.1:p.Cys121Tyr
NP_001182728.1:p.Cys80Tyr
LRG_274t1:c.362G>A
LRG_274:g.20888G>A
LRG_274p1:p.Cys121Tyr
NC_000019.9:g.11215944G>A
NM_000527.4:c.362G>A
c.362G>A

Protein change:

C121Y

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001712; dbSNP: rs193922571

NCBI 1000 Genomes Browser:

rs193922571

Molecular consequence:

NM_001195800.2:c.314-2124G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1297G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.362G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.362G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.239G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002615954	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Dec 14, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16465405, 18096825, 19318025, 20809525, 23375686 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002615954

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Dec 14, 2020)

germline

clinical testing

PubMed (5)
[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

Six novel mutations of the LDL receptor gene in FH kindred of Sicilian and Paraguayan descent.

Cefalù AB, Barraco G, Noto D, Valenti V, Barbagallo CM, Elisir GD, Cuniberti LA, Werba JP, Libra M, Costa S, Gianguzza F, Notarbartolo A, Travali S, Averna MR.

Int J Mol Med. 2006 Mar;17(3):539-46.

PubMed [citation]

PMID:: 16465405

Femoral atherosclerosis in heterozygous familial hypercholesterolemia: influence of the genetic defect.

Junyent M, Gilabert R, Zambón D, Pocoví M, Mallén M, Cofán M, Núñez I, Civeira F, Tejedor D, Ros E.

Arterioscler Thromb Vasc Biol. 2008 Mar;28(3):580-6. Epub 2007 Dec 20.

PubMed [citation]

PMID:: 18096825

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV002615954.2

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

Description

The p.C121Y variant (also known as c.362G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 362. The cysteine at codon 121, located in LDLR class A repeat 3, is replaced by tyrosine, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). This particular cysteine alteration (also referred to as C100Y) has been detected in FH cohorts and segregated with disease in a family (Cefalù AB et al. Int J Mol Med, 2006 Mar;17:539-46; Junyent M et al. Arterioscler Thromb Vasc Biol, 2008 Mar;28:580-6; Alonso R et al. Clin Biochem, 2009 Jun;42:899-903; Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 3 (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be 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: Jun 23, 2024

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