NM_000527.5(LDLR):c.622G>A (p.Glu208Lys) AND Cardiovascular phenotype

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 30, 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:: RCV002365238.2

Allele description [Variation Report for NM_000527.5(LDLR):c.622G>A (p.Glu208Lys)]

NM_000527.5(LDLR):c.622G>A (p.Glu208Lys)

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.622G>A (p.Glu208Lys)

Other names:

FH Jerusalem

HGVS:

NC_000019.10:g.11105528G>A
NG_009060.1:g.21148G>A
NM_000527.5:c.622G>AMANE SELECT
NM_001195798.2:c.622G>A
NM_001195799.2:c.499G>A
NM_001195800.2:c.314-1864G>A
NM_001195803.2:c.314-1037G>A
NP_000518.1:p.Glu208Lys
NP_000518.1:p.Glu208Lys
NP_001182727.1:p.Glu208Lys
NP_001182728.1:p.Glu167Lys
LRG_274t1:c.622G>A
LRG_274:g.21148G>A
LRG_274p1:p.Glu208Lys
NC_000019.9:g.11216204G>A
NM_000527.4:c.622G>A
c.622G>A

Protein change:

E167K

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001775; dbSNP: rs879254597

NCBI 1000 Genomes Browser:

rs879254597

Molecular consequence:

NM_001195800.2:c.314-1864G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1037G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.622G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.622G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.499G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Cdh9 cadherin 9 [Mus musculus]
Cdh9 cadherin 9 [Mus musculus]
Gene ID:12565

Gene
Homologene neighbors for GEO Profiles (Select 71967516) (0)
GEO Profiles
Homologene neighbors for GEO Profiles (Select 71963723) (0)
GEO Profiles
GID4 GID complex subunit 4 homolog [Homo sapiens]
GID4 GID complex subunit 4 homolog [Homo sapiens]
Gene ID:79018

Gene
Gene Links for GEO Profiles (Select 71974007) (1)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002658498	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Aug 30, 2017)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11810272, 1301956, 18677035, 22390909, 8882879, 9767373 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002658498

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Aug 30, 2017)

germline

clinical testing

PubMed (6)
[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

The molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Defesche JC, Umans-Eckenhausen MW, Kastelein JP.

Hum Genet. 2001 Dec;109(6):602-15. Epub 2001 Nov 9.

PubMed [citation]

PMID:: 11810272

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

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV002658498.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The p.E208K variant (also known as c.622G>A), located in coding exon 4 of the LDLR gene, results from a G to A substitution at nucleotide position 622. The glutamic acid at codon 208 is replaced by lysine, an amino acid with similar properties, and is located in the ligand-binding domain. This alteration, also known as E187K, has been reported in multiple individuals with familial hypercholesterolemia (FH) from a variety of ethnic backgrounds, including an affected father-son pair; compound heterozygote cases with this alteration were also reported (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Reshef A et al. Hum. Genet., 1996 Nov;98:581-6; Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Huijgen R et al. Eur. Heart J., 2012 Sep;33:2325-30). One in vitro study demonstrated a ten-fold reduction in beta-VLDL binding with this alteration (Zhao Z et al. J. Biol. Chem., 2008 Sep;283:26528-37). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be 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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