NM_000527.5(LDLR):c.1013G>A (p.Cys338Tyr) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 2, 2018
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:: RCV002374404.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1013G>A (p.Cys338Tyr)]

NM_000527.5(LDLR):c.1013G>A (p.Cys338Tyr)

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.1013G>A (p.Cys338Tyr)

HGVS:

NC_000019.10:g.11110724G>A
NG_009060.1:g.26344G>A
NM_000527.5:c.1013G>AMANE SELECT
NM_001195798.2:c.1013G>A
NM_001195799.2:c.890G>A
NM_001195800.2:c.509G>A
NM_001195803.2:c.632G>A
NP_000518.1:p.Cys338Tyr
NP_000518.1:p.Cys338Tyr
NP_001182727.1:p.Cys338Tyr
NP_001182728.1:p.Cys297Tyr
NP_001182729.1:p.Cys170Tyr
NP_001182732.1:p.Cys211Tyr
LRG_274t1:c.1013G>A
LRG_274:g.26344G>A
LRG_274p1:p.Cys338Tyr
NC_000019.9:g.11221400G>A
NM_000527.4:c.1013G>A
c.1013G>A

Protein change:

C170Y

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000620;

Molecular consequence:

NM_000527.5:c.1013G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1013G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.890G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.509G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.632G>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
SCV002625208	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 2, 2018)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 10735632, 10924730, 12459547, 21310417, 22698793, 7583548, 9399845 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002625208

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jan 2, 2018)

germline

clinical testing

PubMed (7)
[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

Molecular genetic testing for familial hypercholesterolemia: spectrum of LDL receptor gene mutations in The Netherlands.

Lombardi MP, Redeker EJ, Defesche JC, Kamerling SW, Trip MD, Mannens MM, Havekes LM, Kastelein JJ.

Clin Genet. 2000 Feb;57(2):116-24.

PubMed [citation]

PMID:: 10735632

FH-Freiburg: a novel missense mutation (C317Y) in growth factor repeat A of the low density lipoprotein receptor gene in a German patient with homozygous familial hypercholesterolemia.

Nauck MS, Scharnagl H, Nissen H, Schürmann C, Matern D, Nauck MA, Wieland H, März W.

Atherosclerosis. 2000 Aug;151(2):525-34. Erratum in: Atherosclerosis. 2003 Mar;167(1):173.. Mattern D [corrected to Matern D].

PubMed [citation]

PMID:: 10924730

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV002625208.2

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

Description

The p.C338Y pathogenic mutation (also known as c.1013G>A), located in coding exon 7 of the LDLR gene, results from a G to A substitution at nucleotide position 1013. The cysteine at codon 338 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been reported in individuals with familial hypercholesterolemia (FH), and reduced LDL binding was demonstrated in a study of patient skin fibroblasts (Nauck MS et al. Atherosclerosis, 2000;151:525-34; Du&scaron;ková L et al. Atherosclerosis, 2011;216:139-45). 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 FH (Villéger L et al. Hum Mutat. 2002;20(2):81-7). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the EGF-like 1 domain (Rudenko G et al. Science. 2002;298(5602):2353-8). In addition, alterations at the same amino acid position (C338G, C338R, and C338S) have also been reported in association with FH (Lombardi MP et al. Clin. Genet., 2000;57:116-24; Varret M et al. Nucleic Acids Res., 1998;26:248-52; Maruyama T et al. Arterioscler. Thromb. Vasc. Biol., 1995;15:1713-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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 29, 2024

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