NM_000527.5(LDLR):c.1447T>C (p.Trp483Arg) AND Homozygous familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 19, 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:: RCV004017557.1

Allele description [Variation Report for NM_000527.5(LDLR):c.1447T>C (p.Trp483Arg)]

NM_000527.5(LDLR):c.1447T>C (p.Trp483Arg)

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.1447T>C (p.Trp483Arg)

Other names:

NM_000527.5(LDLR):c.1447T>C

HGVS:

NC_000019.10:g.11113623T>C
NG_009060.1:g.29243T>C
NM_000527.5:c.1447T>CMANE SELECT
NM_001195798.2:c.1447T>C
NM_001195799.2:c.1324T>C
NM_001195800.2:c.943T>C
NM_001195803.2:c.1066T>C
NP_000518.1:p.Trp483Arg
NP_000518.1:p.Trp483Arg
NP_001182727.1:p.Trp483Arg
NP_001182728.1:p.Trp442Arg
NP_001182729.1:p.Trp315Arg
NP_001182732.1:p.Trp356Arg
LRG_274t1:c.1447T>C
LRG_274:g.29243T>C
LRG_274p1:p.Trp483Arg
NC_000019.9:g.11224299T>C
NM_000527.4:c.1447T>C
P01130:p.Trp483Arg
c.1447T>C

Protein change:

W315R

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001430; UniProtKB: P01130#VAR_005392; dbSNP: rs879254905

NCBI 1000 Genomes Browser:

rs879254905

Molecular consequence:

NM_000527.5:c.1447T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1447T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1324T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.943T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1066T>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV004848180	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Mar 19, 2018)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 8535447, 16250003, 21382890, 9039985, 27783906, 27680772, 18700895, 17539906, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004848180

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Mar 19, 2018)

germline

clinical testing

PubMed (9)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Three novel mutations in the EGF precursor homology domain of the low-density lipoprotein receptor gene in Northern Irish patients with familial hypercholesterolemia.

Ward AJ, O'Kane M, Young I, Nicholls DP, Nevin NC, Graham CA.

Hum Mutat. 1995;6(3):254-6. No abstract available.

PubMed [citation]

PMID:: 8535447

Update of the molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Kastelein JJ, Defesche JC.

Hum Mutat. 2005 Dec;26(6):550-6.

PubMed [citation]

PMID:: 16250003

See all PubMed Citations (9)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848180.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

The p.Trp483Arg variant in LDLR has been reported in at least 7 individuals with familial hypercholesterolemia and segregated with disease in 6 affected members of 1 family (Ward 1995, Fouchier 2005, Taylor 2007, Martin 2016). It was absent from large population studies. Computational prediction tools and conservation analysis suggest that the variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Trp483Arg variant is likely pathogenic. ACMG/AMP Criteria applied: PM2; PS4_Moderate; PP1_Moderate; PP3.

#	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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