NM_000527.5(LDLR):c.1329G>C (p.Trp443Cys) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 10, 2021
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:: RCV002379064.3

Allele description [Variation Report for NM_000527.5(LDLR):c.1329G>C (p.Trp443Cys)]

NM_000527.5(LDLR):c.1329G>C (p.Trp443Cys)

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.1329G>C (p.Trp443Cys)

Other names:

FH North Platt

HGVS:

NC_000019.10:g.11113420G>C
NG_009060.1:g.29040G>C
NM_000527.5:c.1329G>CMANE SELECT
NM_001195798.2:c.1329G>C
NM_001195799.2:c.1206G>C
NM_001195800.2:c.825G>C
NM_001195803.2:c.948G>C
NP_000518.1:p.Trp443Cys
NP_000518.1:p.Trp443Cys
NP_001182727.1:p.Trp443Cys
NP_001182728.1:p.Trp402Cys
NP_001182729.1:p.Trp275Cys
NP_001182732.1:p.Trp316Cys
LRG_274t1:c.1329G>C
LRG_274:g.29040G>C
LRG_274p1:p.Trp443Cys
NC_000019.9:g.11224096G>C
NM_000527.4:c.1329G>C
P01130:p.Trp443Cys
c.1329G>C

Protein change:

W275C

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001399; UniProtKB: P01130#VAR_005389; dbSNP: rs879254867

NCBI 1000 Genomes Browser:

rs879254867

Molecular consequence:

NM_000527.5:c.1329G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1329G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1206G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.825G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.948G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

Recent activity

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Homo sapiens SPOC domain containing 1 (SPOCD1), mRNA
Homo sapiens SPOC domain containing 1 (SPOCD1), mRNA
gi|142366582|ref|NM_144569.4|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002691627	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 10, 2021)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 11196104, 11810272, 11845603, 1301956, 15556093, 21382890, 22081141, 22390909, 28458923, 9727746 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002691627

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Apr 10, 2021)

germline

clinical testing

PubMed (10)
[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

Mutations in the low-density-lipoprotein receptor gene in German patients with familial hypercholesterolaemia.

Weiss N, Binder G, Keller C.

J Inherit Metab Dis. 2000 Dec;23(8):778-90.

PubMed [citation]

PMID:: 11196104

The molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Defesche JC, Umans-Eckenhausen MW, Kastelein JP.

Hum Genet. 2001 Dec;109(6):602-15. Epub 2001 Nov 9.

PubMed [citation]

PMID:: 11810272

See all PubMed Citations (10)

Details of each submission

From Ambry Genetics, SCV002691627.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

The p.W443C pathogenic mutation (also known as c.1329G>C), located in coding exon 9 of the LDLR gene, results from a G to C substitution at nucleotide position 1329. The tryptophan at codon 443 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the EGF-like precursor domain. This alteration has been reported (also described as p.W422C and North Platt) in numerous individuals with familial hypercholesterolemia (FH) from a variety of ethnic backgrounds (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Vergotine J et al. S. Afr. Med. J., 2001 Dec;91:1053-9; van der Graaf A et al. Circulation, 2011 Mar;123:1167-73). An alternate change at this nucleotide, c.1329G>T, with the same amino acid substitution has also been detected in individuals with FH (Huijgen R et al. Eur. Heart J., 2012 Sep;33:2325-30). Furthermore, additional amino acid substitutions at this position, p.W443S and p.W443R, have been reported in FH cohorts (Sozen M et al. Atheroscler Suppl, 2004 Dec;5:7-11; Korneva VA et al. Cholesterol, 2017 Mar;2017:9375818). Internal structural analysis has also determined that this alteration disrupts the structure in a structural hotspot cluster (Lo Surdo P et al. EMBO Rep., 2011 Dec;12:1300-5). 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: Oct 20, 2024

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