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

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 15, 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:: RCV002415889.2

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]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Platr26 pluripotency associated transcript 26 [Mus musculus]
Platr26 pluripotency associated transcript 26 [Mus musculus]
Gene ID:381371

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002718691	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Dec 15, 2021)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 1301956, 16389549, 17094996, 22883975, 27680772, 27765764, 32041611, 34037665 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002718691

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Dec 15, 2021)

germline

clinical testing

PubMed (8)
[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 genetics of the LDL receptor gene in familial hypercholesterolemia.

Hobbs HH, Brown MS, Goldstein JL.

Hum Mutat. 1992;1(6):445-66. Review.

PubMed [citation]

PMID:: 1301956

Mutational analysis in UK patients with a clinical diagnosis of familial hypercholesterolaemia: relationship with plasma lipid traits, heart disease risk and utility in relative tracing.

Humphries SE, Cranston T, Allen M, Middleton-Price H, Fernandez MC, Senior V, Hawe E, Iversen A, Wray R, Crook MA, Wierzbicki AS.

J Mol Med (Berl). 2006 Mar;84(3):203-14. Epub 2005 Dec 31.

PubMed [citation]

PMID:: 16389549

See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV002718691.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The p.C677R pathogenic mutation (also known as c.2029T>C), located in coding exon 14 of the LDLR gene, results from a T to C substitution at nucleotide position 2029. The cysteine at codon 677 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration was detected in conjunction with another alteration in the LDLR gene in an individual whose protein activity was 5-15% of normal (Hobbs HH et al. Hum Mutat. 1992;1(6):445-66). Subsequent studies observed this alteration in several individuals diagnosed with familial hypercholesterolemia (FH) (Humphries SE et al. J Mol Med. 2006; 84(3):203-14; Tosi I et al. Atherosclerosis. 2007;194(1):102-11). In a case report, this alteration was described to co-segregate with FH in multiple individuals in one family (Bima AI et al. Ann Clin Biochem. 2009;46(Pt 5):420-2). Another alteration affecting the same codon (p.C677Y c.2030G>A) has also been described in patients with FH (Salazar LA et al. Hum Mutat. 2002;19(4):462-3). Based on the supporting evidence, p.C677R 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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