NM_000527.5(LDLR):c.2312-3C>A AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: May 24, 2021
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:: RCV000211656.16

Allele description [Variation Report for NM_000527.5(LDLR):c.2312-3C>A]

NM_000527.5(LDLR):c.2312-3C>A

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.2312-3C>A

HGVS:

NC_000019.10:g.11128005C>A
NG_009060.1:g.43625C>A
NM_000527.5:c.2312-3C>AMANE SELECT
NM_001195798.2:c.2312-3C>A
NM_001195799.2:c.2189-3C>A
NM_001195800.2:c.1808-3C>A
NM_001195803.2:c.1778-3C>A
LRG_274t1:c.2312-3C>A
LRG_274:g.43625C>A
NC_000019.9:g.11238681C>A
NM_000527.4:c.2312-3C>A
c.2312-3C>A
p.(Ala771_Ile796del)

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000948;

Molecular consequence:

NM_000527.5:c.2312-3C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195798.2:c.2312-3C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195799.2:c.2189-3C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195800.2:c.1808-3C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.1778-3C>A - intron variant - [Sequence Ontology: SO:0001627]

Observations:

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

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Tshb thyroid stimulating hormone, beta subunit [Mus musculus]
Tshb thyroid stimulating hormone, beta subunit [Mus musculus]
Gene ID:22094

Gene
22094[uid] AND (alive[prop]) (1)
Gene
PIGF [Papio anubis]
PIGF [Papio anubis]
Gene ID:101023799

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000268664	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	no assertion criteria provided	Pathogenic (Jul 24, 2009)	germline	clinical testing
SCV000295947	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] 11317362, 11668640, 12417285 Citation Link,
SCV000588653	Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (4) [See all records that cite these PMIDs] 25741868, 11317362, 20045108, 21865347
SCV000606631	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV000987039	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 22, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001653659	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 24, 2021)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 11317362, 12628589, 16115486, 21865347, 28965616, 30710474, 32331935, 31491741, 25525159, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	6	not provided	not provided	5	not provided	clinical testing, literature only, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	research
Caucasian	germline	yes	39	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular genetics of familial hypercholesterolemia in Spain: Ten novel LDLR mutations and population analysis.

García-García AB, Real JT, Puig O, Cebolla E, Marín-García P, Martínez Ferrandis JI, García-Sogo M, Civera M, Ascaso JF, Carmena R, Armengod ME, Chaves FJ.

Hum Mutat. 2001 Nov;18(5):458-9.

PubMed [citation]

PMID:: 11668640

Molecular genetic analysis of familial hypercholesterolemia: spectrum and regional difference of LDL receptor gene mutations in Japanese population.

Yu W, Nohara A, Higashikata T, Lu H, Inazu A, Mabuchi H.

Atherosclerosis. 2002 Dec;165(2):335-42. Erratum in: Atherosclerosis. 2004 Jun;174(2):399-400.

PubMed [citation]

PMID:: 12417285

See all PubMed Citations (14)

Details of each submission

From Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268664.1

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

From LDLR-LOVD, British Heart Foundation, SCV000295947.2

#	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 Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil, SCV000588653.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (4)
2	not provided	not provided	not provided	not provided	research	PubMed (4)

Description

"Assay description:Htz patients' lymphocytes / Htz Epstein-Barr transformed lymphocytes cells, RNA and FACS assays"

PubMed [ID: 11317362]

#	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
2	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606631.1

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

#	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 Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen, SCV000987039.1

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

Description

The mutation leads to a change in the splice acceptor in intron 15 of the LDLR gene. It has already been described in the literature, detected in patients with familial hypercholesterolemia, and associated with elevated cholesterol and LDL-C levels. In in vitro models, the mutation leads to almost complete loss of LDL receptor activity. We observed this mutation in a patient with TC up to 520 mg/dl and LDL-C approx 420 mg/dl at the age of 45 years. PMID: 11317362, 21865347

#	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

From Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia, SCV001432564.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (2)
2	not provided	1	not provided	not provided	research	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 Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II, SCV001653659.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	39	not provided	not provided	clinical testing	PubMed (10)

Description

Reduced activity, in stimulated T-lymphocytes and EBV-transformed B-lymphocytes.

#	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		39	not provided	not provided	not provided

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001432564	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (ACMG Guidelines, 2015)	Uncertain significance (Jun 17, 2019)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31345425

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001432564

Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 17, 2019)

germline

research

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

Last Updated: Sep 29, 2024

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