NM_000527.5(LDLR):c.1019_1020delinsTG (p.Cys340Leu) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 13, 2022
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:: RCV001203165.8

Allele description [Variation Report for NM_000527.5(LDLR):c.1019_1020delinsTG (p.Cys340Leu)]

NM_000527.5(LDLR):c.1019_1020delinsTG (p.Cys340Leu)

Gene:

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

Variant type:

Indel

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.5(LDLR):c.1019_1020delinsTG (p.Cys340Leu)

HGVS:

NC_000019.10:g.11110730_11110731delinsTG
NG_009060.1:g.26350_26351delinsTG
NM_000527.5:c.1019_1020delinsTGMANE SELECT
NM_001195798.2:c.1019_1020delinsTG
NM_001195799.2:c.896_897delinsTG
NM_001195800.2:c.515_516delinsTG
NM_001195803.2:c.638_639delinsTG
NP_000518.1:p.Cys340Leu
NP_001182727.1:p.Cys340Leu
NP_001182728.1:p.Cys299Leu
NP_001182729.1:p.Cys172Leu
NP_001182732.1:p.Cys213Leu
LRG_274:g.26350_26351delinsTG
NC_000019.9:g.11221406_11221407delinsTG
c.1019_1020delinsTG

Protein change:

C172L

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001324; dbSNP: rs879254758

NCBI 1000 Genomes Browser:

rs879254758

Molecular consequence:

NM_000527.5:c.1019_1020delinsTG - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1019_1020delinsTG - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.896_897delinsTG - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.515_516delinsTG - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.638_639delinsTG - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia
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
SCV001374316	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 13, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 7548065, 7603991, 7979249, 18325082, 20809525, 23535506, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001374316

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 13, 2022)

germline

clinical testing

PubMed (7)
[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

Disulfide bridges of a cysteine-rich repeat of the LDL receptor ligand-binding domain.

Bieri S, Djordjevic JT, Daly NL, Smith R, Kroon PA.

Biochemistry. 1995 Oct 10;34(40):13059-65.

PubMed [citation]

PMID:: 7548065

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

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001374316.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

For these reasons, this variant has been classified as Pathogenic. 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). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 251599). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 20809525, 23535506). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.08%). This sequence change replaces cysteine, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 340 of the LDLR protein (p.Cys340Leu).

#	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: Sep 29, 2024

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