NM_000527.5(LDLR):c.1988-2A>G AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 16, 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:: RCV000417318.3

Allele description [Variation Report for NM_000527.5(LDLR):c.1988-2A>G]

NM_000527.5(LDLR):c.1988-2A>G

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.1988-2A>G

HGVS:

NC_000019.10:g.11120368A>G
NG_009060.1:g.35988A>G
NM_000527.5:c.1988-2A>GMANE SELECT
NM_001195798.2:c.1988-2A>G
NM_001195799.2:c.1865-2A>G
NM_001195800.2:c.1484-2A>G
NM_001195803.2:c.1606+135A>G
LRG_274t1:c.1988-2A>G
LRG_274:g.35988A>G
NC_000019.9:g.11231044A>G
NM_000527.4:c.1988-2A>G

Links:

dbSNP: rs879255101

NCBI 1000 Genomes Browser:

rs879255101

Molecular consequence:

NM_001195803.2:c.1606+135A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.1988-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195798.2:c.1988-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195799.2:c.1865-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001195800.2:c.1484-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000503448	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000987016	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 16, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000503448

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 16, 2016)

germline

clinical testing

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

SCV000987016

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

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 16, 2018)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	2600	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503448.1

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

Description

subject mutated among 2600 FH index cases screened = 1

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	2600	not provided	not provided		1	not provided	not provided	not provided

From Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen, SCV000987016.1

#	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 alteration of the nearly invariant dinucleotide "AG" of the 3 'splice site consensus sequence in the intron. Alteration of this dinucleotide leads to an error in the splicing of the RNA. This mutation has already been described in patients with hypercholesterolemia and is therefore classified as pathogenic. This variant was observed in a patient with TC approx. 250 mg/dl and LDL-C approx 200 mg/dl at the age of 30. PMID: 17964958, 23375686

#	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

Last Updated: Jun 23, 2024

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