NM_000527.5(LDLR):c.1329G>C (p.Trp443Cys) AND Homozygous familial hypercholesterolemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 31, 2017
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:: RCV000844741.5

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]

Observations:

Condition(s)

Name:: Homozygous familial hypercholesterolemia
Synonyms:: Familial hypercholesterolemia - homozygous
Identifiers:: MONDO: MONDO:0018328; MedGen: C0342881

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000731444	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Jan 31, 2017)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 21382890, 22390909, 9727746, 1301956, 11810272, 11196104, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000731444

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Jan 31, 2017)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	5	5	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children.

van der Graaf A, Avis HJ, Kusters DM, Vissers MN, Hutten BA, Defesche JC, Huijgen R, Fouchier SW, Wijburg FA, Kastelein JJ, Wiegman A.

Circulation. 2011 Mar 22;123(11):1167-73. doi: 10.1161/CIRCULATIONAHA.110.979450. Epub 2011 Mar 7.

PubMed [citation]

PMID:: 21382890

Cardiovascular risk in relation to functionality of sequence variants in the gene coding for the low-density lipoprotein receptor: a study among 29,365 individuals tested for 64 specific low-density lipoprotein-receptor sequence variants.

Huijgen R, Kindt I, Defesche JC, Kastelein JJ.

Eur Heart J. 2012 Sep;33(18):2325-30. doi: 10.1093/eurheartj/ehs038. Epub 2012 Mar 4.

PubMed [citation]

PMID:: 22390909

See all PubMed Citations (7)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000731444.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (7)

Description

The p.Trp443Cys variant in LDLR has been reported in >90 individuals with famili al hypercholesterolemia (FH) and was absent from large population studies. In vi tro functional studies demonstrate that this variant results in reduced protein activity (Hobbs 1992). Computational prediction tools and conservation analysis suggest that the p.Trp443Cys variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dom inant manner based upon prevalence among probands, absence from controls, and fu nctional evidence.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		5	not provided	5	not provided

Last Updated: Oct 20, 2024

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