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

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:
RCV000775039.9

Allele description [Variation Report for NM_000527.5(LDLR):c.427T>C (p.Cys143Arg)]

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000909136Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Mar 12, 2019)
germlineclinical testing

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

SCV001580452Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jan 11, 2023)
germlineclinical testing

PubMed (10)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001580452.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

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

Last Updated: Sep 29, 2024