NM_000527.5(LDLR):c.590G>T (p.Cys197Phe) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 23, 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:: RCV002356330.2

Allele description [Variation Report for NM_000527.5(LDLR):c.590G>T (p.Cys197Phe)]

NM_000527.5(LDLR):c.590G>T (p.Cys197Phe)

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.590G>T (p.Cys197Phe)

Other names:

FH Shreveport; NM_000527.5(LDLR):c.590G>T

HGVS:

NC_000019.10:g.11105496G>T
NG_009060.1:g.21116G>T
NM_000527.5:c.590G>TMANE SELECT
NM_001195798.2:c.590G>T
NM_001195799.2:c.467G>T
NM_001195800.2:c.314-1896G>T
NM_001195803.2:c.314-1069G>T
NP_000518.1:p.Cys197Phe
NP_000518.1:p.Cys197Phe
NP_001182727.1:p.Cys197Phe
NP_001182728.1:p.Cys156Phe
LRG_274t1:c.590G>T
LRG_274:g.21116G>T
NC_000019.9:g.11216172G>T
NM_000527.4(LDLR):c.590G>T
NM_000527.4:c.590G>T
P01130:p.Cys197Phe
c.590G>T

Protein change:

C156F

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000082; UniProtKB: P01130#VAR_005328; dbSNP: rs376459828

NCBI 1000 Genomes Browser:

rs376459828

Molecular consequence:

NM_001195800.2:c.314-1896G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1069G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.590G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.590G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.467G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002652596	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 23, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 1301956, 20828696 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002652596

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jan 23, 2018)

germline

clinical testing

PubMed (2)
[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

Update of the Portuguese Familial Hypercholesterolaemia Study.

Medeiros AM, Alves AC, Francisco V, Bourbon M; investigators of the Portuguese FH Study..

Atherosclerosis. 2010 Oct;212(2):553-8. doi: 10.1016/j.atherosclerosis.2010.07.012. Epub 2010 Aug 8.

PubMed [citation]

PMID:: 20828696

Details of each submission

From Ambry Genetics, SCV002652596.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.C197F pathogenic mutation (also known as c.590G>T), located in coding exon 4 of the LDLR gene, results from a G to T substitution at nucleotide position 590. The cysteine at codon 197, located in LDLR class A repeat 5, is replaced by phenylalanine, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). This alteration, also referred to as FH Shreveport or C176F, has been reported in association with FH (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Medeiros AM et al. Atherosclerosis, 2010 Oct;212:553-8). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 5. In addition, other alterations affecting this amino acid (C197Y, C197W, C197G, C197R) have also been described in association with FH (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Chmara M et al. J Appl Genet. 2010;51(1):95-106; Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24; Webb JC et al. J. Lipid Res., 1996 Feb;37:368-81). 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: Sep 29, 2024

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