NM_000527.5(LDLR):c.1518_1586+340del AND Familial hypercholesterolemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 15, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003742137.1

Allele description [Variation Report for NM_000527.5(LDLR):c.1518_1586+340del]

NM_000527.5(LDLR):c.1518_1586+340del

Gene:

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

Variant type:

Deletion

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.5(LDLR):c.1518_1586+340del

HGVS:

NC_000019.10:g.11113694_11114102del
NG_009060.1:g.29314_29722del
NM_000527.5:c.1518_1586+340delMANE SELECT
NM_001195798.2:c.1518_1586+340del
NM_001195799.2:c.1395_1463+340del
NM_001195800.2:c.1014_1082+340del
NM_001195803.2:c.1137_1205+340del
LRG_274:g.29314_29722del
NC_000019.9:g.11224367_11224775del
NC_000019.9:g.11224370_11224778del

Molecular consequence:

NM_000527.5:c.1518_1586+340del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195798.2:c.1518_1586+340del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195799.2:c.1395_1463+340del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195800.2:c.1014_1082+340del - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195803.2:c.1137_1205+340del - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Familial hypercholesterolemia (FH)
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004447831	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 15, 2023)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 2088165, 14974088, 15256764, 21310417, 21865347, 22294733, 23375686, 25463123, 27765764, 16199547, 20809525, 28645073, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004447831

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 15, 2023)

germline

clinical testing

PubMed (13)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein.

Hobbs HH, Russell DW, Brown MS, Goldstein JL.

Annu Rev Genet. 1990;24:133-70. Review. No abstract available.

PubMed [citation]

PMID:: 2088165

Molecular characterization of familial hypercholesterolemia in German and Greek patients.

Dedoussis GV, Genschel J, Bochow B, Pitsavos C, Skoumas J, Prassa M, Lkhagvasuren S, Toutouzas P, Vogt A, Kassner U, Thomas HP, Schmidt H.

Hum Mutat. 2004 Mar;23(3):285-6.

PubMed [citation]

PMID:: 14974088

See all PubMed Citations (13)

Details of each submission

From Invitae, SCV004447831.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the LDLR protein in which other variant(s) (p.Val523Met) have been determined to be pathogenic (PMID: 2088165, 14974088, 15256764, 21310417, 21865347, 22294733, 23375686, 25463123, 27765764). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with LDLR-related conditions. This variant results in the deletion of part of exon 10 (c.1518_1586+340del) of the LDLR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073).

#	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: Feb 28, 2024

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