NM_000527.5(LDLR):c.1735G>A (p.Asp579Asn) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Oct 19, 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:: RCV000237346.5

Allele description [Variation Report for NM_000527.5(LDLR):c.1735G>A (p.Asp579Asn)]

NM_000527.5(LDLR):c.1735G>A (p.Asp579Asn)

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.1735G>A (p.Asp579Asn)

Other names:

FH Cincinnati-4

HGVS:

NC_000019.10:g.11116888G>A
NG_009060.1:g.32508G>A
NM_000527.5:c.1735G>AMANE SELECT
NM_001195798.2:c.1735G>A
NM_001195799.2:c.1612G>A
NM_001195800.2:c.1231G>A
NM_001195803.2:c.1354G>A
NP_000518.1:p.Asp579Asn
NP_000518.1:p.Asp579Asn
NP_001182727.1:p.Asp579Asn
NP_001182728.1:p.Asp538Asn
NP_001182729.1:p.Asp411Asn
NP_001182732.1:p.Asp452Asn
LRG_274t1:c.1735G>A
LRG_274:g.32508G>A
LRG_274p1:p.Asp579Asn
NC_000019.9:g.11227564G>A
NM_000527.4:c.1735G>A
P01130:p.Asp579Asn
c.1735G>A

Protein change:

D411N

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001510; UniProtKB: P01130#VAR_005402; dbSNP: rs875989929

NCBI 1000 Genomes Browser:

rs875989929

Molecular consequence:

NM_000527.5:c.1735G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1735G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1612G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1231G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1354G>A - missense variant - [Sequence Ontology: SO:0001583]

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

Recent activity

Clear Turn Off Turn On

CBXT1314.g1 NICHD_XGC_trop_25 Xenopus tropicalis cDNA clone IMAGE:8883235 3', mR...
CBXT1314.g1 NICHD_XGC_trop_25 Xenopus tropicalis cDNA clone IMAGE:8883235 3', mRNA sequence
gi|133804107|gnl|dbEST|45233711|gb| 751.1|

Nucleotide

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295624	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] 10532689, 1301956, 7635461 Citation Link,
SCV000914826	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Oct 19, 2018)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16542394, 7635461, 11373616, 11585102, 1301956 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000295624

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]

Citation Link,

SCV000914826

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Pathogenic
(Oct 19, 2018)

germline

clinical testing

PubMed (5)
[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	yes	3	not provided	not provided	3	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Spectrum of LDL receptor gene mutations in Denmark: implications for molecular diagnostic strategy in heterozygous familial hypercholesterolemia.

Jensen HK, Jensen LG, Meinertz H, Hansen PS, Gregersen N, Faergeman O.

Atherosclerosis. 1999 Oct;146(2):337-44.

PubMed [citation]

PMID:: 10532689

Molecular genetic analysis of 1053 Danish individuals with clinical signs of familial hypercholesterolemia.

Brusgaard K, Jordan P, Hansen H, Hansen AB, Hørder M.

Clin Genet. 2006 Mar;69(3):277-83.

PubMed [citation]

PMID:: 16542394

See all PubMed Citations (6)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295624.2

#	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 Illumina Laboratory Services, Illumina, SCV000914826.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Across a selection of available literature, the LDLR c.1735G>A (p.Asp579Asn) variant, also known as p.Asp558Asn, has been reported in at least five studies and is found in at least seven probands with familial hypercholesterolemia in a heterozygous state (Hobbs et al. 1992; Ekstrom et al. 1995; Vuorio et al. 2001; Brusgaard et al. 2006). Control data are unavailable for this variant and it is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium or the Genome Aggregation Database, with good sequence coverage of this region, and therefore it is presumed to be rare. Functional studies in cultured proband fibroblasts demonstrated that the p.Asp579Asn variant protein had 52% LDL binding, 42% internalization, and 46% degradation compared to control fibroblasts, suggesting that it had a binding-defective phenotype (Vuorio et al. 2001). Expression analysis in proband fibroblasts also found p.Asp579Asn to have 2% LDL receptor activity compared to controls (Hobbs et al. 1992). The Asp579 residue is highly conserved across species and x-ray crystallography demonstrated the importance of the Asp579 residue in hydrogen bonding necessary for structural formation (Ekstrom et al. 1995; Jeon et al. 2001). Based on the evidence, the p.Asp579Asn variant is classified as pathogenic for familial hypercholesterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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

ClinVar

Relating variation to medicine