NM_000527.5(LDLR):c.692G>A (p.Cys231Tyr) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 25, 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:: RCV003581608.2

Allele description [Variation Report for NM_000527.5(LDLR):c.692G>A (p.Cys231Tyr)]

NM_000527.5(LDLR):c.692G>A (p.Cys231Tyr)

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.692G>A (p.Cys231Tyr)

HGVS:

NC_000019.10:g.11105598G>A
NG_009060.1:g.21218G>A
NM_000527.5:c.692G>AMANE SELECT
NM_001195798.2:c.692G>A
NM_001195799.2:c.569G>A
NM_001195800.2:c.314-1794G>A
NM_001195803.2:c.314-967G>A
NP_000518.1:p.Cys231Tyr
NP_000518.1:p.Cys231Tyr
NP_001182727.1:p.Cys231Tyr
NP_001182728.1:p.Cys190Tyr
LRG_274t1:c.692G>A
LRG_274:g.21218G>A
LRG_274p1:p.Cys231Tyr
NC_000019.9:g.11216274G>A
NM_000527.4:c.692G>A
c.692G>A

Protein change:

C190Y

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000108; dbSNP: rs879254644

NCBI 1000 Genomes Browser:

rs879254644

Molecular consequence:

NM_001195800.2:c.314-1794G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-967G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.692G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.692G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.569G>A - 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
SCV004298332	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 25, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 10782930, 7548065, 7603991, 7979249, 18325082, 19073363, 27830735, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004298332

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 25, 2023)

germline

clinical testing

PubMed (8)
[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

Identification of four novel mutations of the low-density lipoprotein receptor gene in Korean patients with familial hypercholesterolemia.

Shin JA, Kim SH, Kim UK, Chae JJ, Choe SJ, Namkoong Y, Kim HS, Park YB, Lee CC.

Clin Genet. 2000 Mar;57(3):225-9.

PubMed [citation]

PMID:: 10782930

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

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004298332.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 10782930). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 251398). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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). This variant disrupts the p.Cys231 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19073363, 27830735; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 231 of the LDLR protein (p.Cys231Tyr).

#	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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