NM_000527.4(LDLR):c.662A>G (p.Asp221Gly) AND Familial hypercholesterolemia

This record was updated by the submitter. Please see the current version.

Germline classification:: Conflicting classifications of pathogenicity (3 submissions)
Last evaluated:: Mar 25, 2016
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:: RCV000211655.3

Allele description

NM_000527.4(LDLR):c.662A>G (p.Asp221Gly)

Gene:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.4(LDLR):c.662A>G (p.Asp221Gly)

Other names:

FH Padova-1

HGVS:

NC_000019.10:g.11105568A>G
NG_009060.1:g.21188A>G
NM_000527.4:c.662A>G
NM_001195800.1:c.314-1824A>G
NP_000518.1:p.Asp221Gly
LRG_274t1:c.662A>G
LRG_274:g.21188A>G
LRG_274p1:p.Asp221Gly
NC_000019.9:g.11216244A>G
P01130:p.Asp221Gly
c.662A>G

Protein change:

D221G

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000096; UniProtKB: P01130#VAR_005332; dbSNP: rs373822756

NCBI 1000 Genomes Browser:

rs373822756

Allele Frequency:

0.00008(G)

Molecular consequence:

NM_001195800.1:c.314-1824A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.4:c.662A>G - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

has functional consequence - Comment(s)

Observations:

Condition(s)

Name:: Familial hypercholesterolemia (FH)
Synonyms:: LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:: MedGen: C0020445; Orphanet: 391665; OMIM: 143890
Prevalence:: 1-9 / 1 000 000 391665

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000268577	Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital	no assertion criteria provided	Pathogenic (Dec 12, 2009)	germline	clinical testing
SCV000294862	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Variant Guidelines, 2015)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (8) [See all records that cite these PMIDs] 10208479, 10978268, 1301956, 7649546, 9104431, 17765246, 20145306, 21310417 Citation Link,
SCV000322908	Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge	criteria provided, single submitter (ACMG guidelines, 2015)	Pathogenic (Mar 1, 2016)	germline	research	PubMed (3) [See all records that cite these PMIDs] 25741868, 1301956, 9974426

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000268577

Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital

no assertion criteria provided

Pathogenic
(Dec 12, 2009)

germline

clinical testing

SCV000294862

LDLR-LOVD, British Heart Foundation

criteria provided, single submitter

(ACGS Variant Guidelines, 2015)

Likely pathogenic
(Mar 25, 2016)

germline

literature only

PubMed (8)
[See all records that cite these PMIDs]

Citation Link,

SCV000322908

Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge

criteria provided, single submitter

(ACMG guidelines, 2015)

Pathogenic
(Mar 1, 2016)

germline

research

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	11	not provided	not provided	8	not provided	clinical testing, research, literature only

Citations

PubMed

The type of mutation in the low density lipoprotein receptor gene influences the cholesterol-lowering response of the HMG-CoA reductase inhibitor simvastatin in patients with heterozygous familial hypercholesterolaemia.

Heath KE, Gudnason V, Humphries SE, Seed M.

Atherosclerosis. 1999 Mar;143(1):41-54.

PubMed [citation]

PMID:: 10208479

Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype.

Bertolini S, Cantafora A, Averna M, Cortese C, Motti C, Martini S, Pes G, Postiglione A, Stefanutti C, Blotta I, Pisciotta L, Rolleri M, Langheim S, Ghisellini M, Rabbone I, Calandra S.

Arterioscler Thromb Vasc Biol. 2000 Sep;20(9):E41-52.

PubMed [citation]

PMID:: 10978268

See all PubMed Citations (10)

Details of each submission

From Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268577.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		3	not provided	not provided	not provided

From LDLR-LOVD, British Heart Foundation, SCV000294862.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (8)
2	not provided	1	not provided	not provided	literature only	PubMed (8)
3	not provided	1	not provided	not provided	literature only	PubMed (8)
4	not provided	1	not provided	not provided	literature only	PubMed (8)
5	not provided	1	not provided	not provided	literature only	PubMed (8)
6	not provided	1	not provided	not provided	literature only	PubMed (8)
7	not provided	1	not provided	not provided	literature only	PubMed (8)
8	not provided	1	not provided	not provided	literature only	PubMed (8)

#	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
4	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
5	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
6	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
7	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
8	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge, SCV000322908.1

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

Description

%MAF (ExAC):0.008407

"Compound Heterozygous (with p.(Gly549Asp)) / Homozygous patients' fibroblasts, 125I-LDL assays"

PubMed [ID: 1301956]

Description

0/190 non-FH alleles; 0/60 healthy control individuals

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided
2	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Dec 6, 2016

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