NM_000527.5(LDLR):c.2029T>C (p.Cys677Arg) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely pathogenic (4 submissions)
Last evaluated:: Apr 13, 2018
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000211671.11

Allele description [Variation Report for NM_000527.5(LDLR):c.2029T>C (p.Cys677Arg)]

NM_000527.5(LDLR):c.2029T>C (p.Cys677Arg)

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.2029T>C (p.Cys677Arg)

Other names:

FH New York-3; NP_000518.1:p.C677R

HGVS:

NC_000019.10:g.11120411T>C
NG_009060.1:g.36031T>C
NM_000527.5:c.2029T>CMANE SELECT
NM_001195798.2:c.2029T>C
NM_001195799.2:c.1906T>C
NM_001195800.2:c.1525T>C
NM_001195803.2:c.1606+178T>C
NP_000518.1:p.Cys677Arg
NP_000518.1:p.Cys677Arg
NP_001182727.1:p.Cys677Arg
NP_001182728.1:p.Cys636Arg
NP_001182729.1:p.Cys509Arg
LRG_274t1:c.2029T>C
LRG_274:g.36031T>C
LRG_274p1:p.Cys677Arg
NC_000019.9:g.11231087T>C
NM_000527.4:c.2029T>C
P01130:p.Cys677Arg
c.2029T>C

Protein change:

C509R

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001587; UniProtKB: P01130#VAR_005408; dbSNP: rs775092314

NCBI 1000 Genomes Browser:

rs775092314

Molecular consequence:

NM_001195803.2:c.1606+178T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.2029T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.2029T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1906T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1525T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hypercholesterolemia, familial, 1
Synonyms:: LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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MeSH
Gene neighbors for Gene (Select 5886) (34)
Gene
dbVar for Gene (Select 8175) (280)
dbVar
RecName: Full=UV excision repair protein RAD23 homolog A; Short=HR23A; Short=hHR...
RecName: Full=UV excision repair protein RAD23 homolog A; Short=HR23A; Short=hHR23A
gi|1709983|sp|P54725.1|RD23A_HUMAN

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000268653	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	no assertion criteria provided	Pathogenic (Jun 5, 2008)	germline	clinical testing
SCV000295824	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 10208479, 10559517, 1301956 Citation Link,
SCV000484752	Robarts Research Institute, Western University	criteria provided, single submitter (Wang et al. (Arterioscler Thromb Vasc Biol. 2016))	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000839986	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 13, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	8	not provided	not provided	3	not provided	clinical testing, literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The type of mutation in the low density lipoprotein receptor gene influences the cholesterol-lowering response of the HMG-CoA reductase inhibitor simvastatin in patients with heterozygous familial hypercholesterolaemia.

Heath KE, Gudnason V, Humphries SE, Seed M.

Atherosclerosis. 1999 Mar;143(1):41-54.

PubMed [citation]

PMID:: 10208479

Mutation screening and genotype:phenotype correlation in familial hypercholesterolaemia.

Graham CA, McClean E, Ward AJ, Beattie ED, Martin S, O'Kane M, Young IS, Nicholls DP.

Atherosclerosis. 1999 Dec;147(2):309-16.

PubMed [citation]

PMID:: 10559517

See all PubMed Citations (5)

Details of each submission

From Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268653.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		4	not provided	not provided	not provided

From LDLR-LOVD, British Heart Foundation, SCV000295824.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (3)
2	not provided	1	not provided	not provided	literature only	PubMed (3)
3	not provided	1	not provided	not provided	literature only	PubMed (3)

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

From Robarts Research Institute, Western University, SCV000484752.1

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

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

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV000839986.1

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

Description

This c.2029T>C (p.Cys677Arg) variant in the LDLR gene has been reported in multiple individuals with familial hypercholesterolemia (PMID: 1301956, 10208479, 10559517) or myocardial infarction (PMID 25487149). Functional studies have indicated that the p.Cys677Arg variant in the LDLR protein has 5-15% receptor activity compared to wild-type LDLR protein (PMID: 1301956). The c.2029T>C variant is rare in the general population and cysteine at position 677 of the LDLR protein is highly evolutionarily conserved. The c.2029T>C (p.Cys677Arg) variant in the LDLR gene is classified as likely 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: Sep 29, 2024

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