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NM_000527.5(LDLR):c.191-732_740del AND Familial hypercholesterolemia

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Nov 1, 2019
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:
RCV001219437.2

Allele description [Variation Report for NM_000527.5(LDLR):c.191-732_740del]

NM_000527.5(LDLR):c.191-732_740del

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.191-732_740del
HGVS:
  • NC_000019.10:g.11101929_11106607del
  • NC_000019.10:g.11101932_11106610del
  • NG_009060.1:g.17552_22230del
  • NM_000527.5:c.191-732_740delMANE SELECT
  • NM_001195798.2:c.191-732_740del
  • NM_001195799.2:c.190+1587_617del
  • NM_001195800.2:c.191-732_314-782del
  • NM_001195803.2:c.191-732_359del
  • LRG_274t1:c.191-735_737del
  • LRG_274:g.17552_22230del
  • NC_000019.9:g.11212608_11217286del
  • NM_000527.4:c.191-735_737del
Molecular consequence:
  • NM_000527.5:c.191-732_740del - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001195798.2:c.191-732_740del - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001195799.2:c.190+1587_617del - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001195800.2:c.191-732_314-782del - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001195803.2:c.191-732_359del - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_000527.5:c.191-732_740del - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001195798.2:c.191-732_740del - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001195799.2:c.190+1587_617del - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001195800.2:c.191-732_314-782del - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001195803.2:c.191-732_359del - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

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

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001391375Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Nov 1, 2019) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor.

Daly NL, Scanlon MJ, Djordjevic JT, Kroon PA, Smith R.

Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6334-8.

PubMed [citation]
PMID:
7603991
PMCID:
PMC41512

Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP).

Krieger M, Herz J.

Annu Rev Biochem. 1994;63:601-37. Review. No abstract available.

PubMed [citation]
PMID:
7979249
See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001391375.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This variant is a deletion of the genomic region encompassing exons 3-4 and part of exon 5 (c.191-735_737del) of the LDLR gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with LDLR-related conditions. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024