NM_000527.5(LDLR):c.427T>C (p.Cys143Arg) AND Familial hypercholesterolemia

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 11, 2023
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:: RCV000775039.8

Allele description

NM_000527.5(LDLR):c.427T>C (p.Cys143Arg)

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.427T>C (p.Cys143Arg)

HGVS:

NC_000019.10:g.11105333T>C
NG_009060.1:g.20953T>C
NM_000527.5:c.427T>CMANE SELECT
NM_001195798.2:c.427T>C
NM_001195799.2:c.304T>C
NM_001195800.2:c.314-2059T>C
NM_001195803.2:c.314-1232T>C
NP_000518.1:p.Cys143Arg
NP_000518.1:p.Cys143Arg
NP_001182727.1:p.Cys143Arg
NP_001182728.1:p.Cys102Arg
LRG_274t1:c.427T>C
LRG_274:g.20953T>C
LRG_274p1:p.Cys143Arg
NC_000019.9:g.11216009T>C
NM_000527.4:c.427T>C
P01130:p.Cys143Arg
c.427T>C

Protein change:

C102R

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000058; UniProtKB: P01130#VAR_072828; dbSNP: rs875989901

NCBI 1000 Genomes Browser:

rs875989901

Molecular consequence:

NM_001195800.2:c.314-2059T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1232T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.427T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.427T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.304T>C - 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
SCV000909136	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 12, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001580452	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 11, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 20828696, 22698793, 11462246, 30270055, 30592178, 7548065, 7603991, 7979249, 18325082, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000909136

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 12, 2019)

germline

clinical testing

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

SCV001580452

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 11, 2023)

germline

clinical testing

PubMed (10)
[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

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

Update of the Portuguese Familial Hypercholesterolaemia Study.

Medeiros AM, Alves AC, Francisco V, Bourbon M; investigators of the Portuguese FH Study..

Atherosclerosis. 2010 Oct;212(2):553-8. doi: 10.1016/j.atherosclerosis.2010.07.012. Epub 2010 Aug 8.

PubMed [citation]

PMID:: 20828696

See all PubMed Citations (11)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000909136.3

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

Description

This missense variant (also known as p.Cys122Arg in the mature protein) is located in the third LDLR type A repeat of the ligand binding domain of the LDLR protein. Although functional studies have not been performed, this variant changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the ligand binding domain (PMID: 15952897) and is expected to have deleterious impact on the LDLR protein folding and stability. Computational splicing tools suggest that this variant may not impact RNA splicing. This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 11462246, 20828696, 21310417, 22698793, 24627126). This variant has been reported in three affected individuals from a Portuguese family (PMID: 24627126) and has also been detected in two affected siblings tested at Color (internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic.

#	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

From Invitae, SCV001580452.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 143 of the LDLR protein (p.Cys143Arg). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11462246, 20828696, 22698793; Invitae). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys143 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11462246, 30270055, 30592178), which suggests that this may be a clinically significant amino acid residue. 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 251219). This variant is also known as C122R.

#	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 1, 2024

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