NM_000527.5(LDLR):c.1586G>A (p.Gly529Asp) AND Hypercholesterolemia, familial, 1

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jan 22, 2020
Review status:: criteria provided, conflicting classifications

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:: RCV000231049.10

Allele description [Variation Report for NM_000527.5(LDLR):c.1586G>A (p.Gly529Asp)]

NM_000527.5(LDLR):c.1586G>A (p.Gly529Asp)

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.1586G>A (p.Gly529Asp)

HGVS:

NC_000019.10:g.11113762G>A
NG_009060.1:g.29382G>A
NM_000527.5:c.1586G>AMANE SELECT
NM_001195798.2:c.1586G>A
NM_001195799.2:c.1463G>A
NM_001195800.2:c.1082G>A
NM_001195803.2:c.1205G>A
NP_000518.1:p.Gly529Asp
NP_000518.1:p.Gly529Asp
NP_001182727.1:p.Gly529Asp
NP_001182728.1:p.Gly488Asp
NP_001182729.1:p.Gly361Asp
NP_001182732.1:p.Gly402Asp
LRG_274t1:c.1586G>A
LRG_274:g.29382G>A
NC_000019.9:g.11224438G>A
NM_000527.4(LDLR):c.1586G>A
NM_000527.4:c.1586G>A
c.1586G>A
p.Gly529Asp

Protein change:

G361D

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001464; dbSNP: rs878854025

NCBI 1000 Genomes Browser:

rs878854025

Molecular consequence:

NM_000527.5:c.1586G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1586G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1463G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1082G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1205G>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

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
SCV000295507	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 21722902, 23375686 Citation Link,
SCV000748056	Iberoamerican FH Network	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV001422782	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 22, 2020)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 22998978, 21722902, 25741868 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000295507

LDLR-LOVD, British Heart Foundation

criteria provided, single submitter

(ACGS Guidelines, 2013)

Likely pathogenic
(Mar 25, 2016)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000748056

Iberoamerican FH Network

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 1, 2016)

germline

research

PubMed (1)
[See all records that cite this PMID]

SCV001422782

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 22, 2020)

germline

curation

PubMed (3)
[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	2	not provided	not provided	2	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	research, curation

Citations

PubMed

Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy.

Bertolini S, Pisciotta L, Rabacchi C, Cefalù AB, Noto D, Fasano T, Signori A, Fresa R, Averna M, Calandra S.

Atherosclerosis. 2013 Apr;227(2):342-8. doi: 10.1016/j.atherosclerosis.2013.01.007. Epub 2013 Jan 19.

PubMed [citation]

PMID:: 23375686

Nutraceutical pill containing berberine versus ezetimibe on plasma lipid pattern in hypercholesterolemic subjects and its additive effect in patients with familial hypercholesterolemia on stable cholesterol-lowering treatment.

Pisciotta L, Bellocchio A, Bertolini S.

Lipids Health Dis. 2012 Sep 22;11:123. doi: 10.1186/1476-511X-11-123.

PubMed [citation]

PMID:: 22998978
PMCID:: PMC3477057

See all PubMed Citations (4)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295507.2

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

#	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

From Iberoamerican FH Network, SCV000748056.1

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

#	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

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422782.2

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

Description

The p.Gly529Asp variant in LDLR has been reported in 2 individuals (including 1 Mexican individual) with Familial Hypercholesterolemia (PMID: 21722902, 22998978), and has been identified in 0.005787% (2/34562) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs878854025). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This splice variant is predicted to cause a deletion of an exon and is not predicted to alter the protein reading-frame. The exon deletion is expected to impact the EGF-precursor homology domain (PMID: 21722902). One VUS with a different amino acid change at the same position, p.Gly529Arg, has been reported in association with disease in ClinVar (Variation ID: 183122). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM4, PS4_Supporting (Richards 2015).

#	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