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NM_000527.5(LDLR):c.244T>G (p.Cys82Gly) AND Familial hypercholesterolemia

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 4, 2021
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:
RCV001857820.3

Allele description

NM_000527.5(LDLR):c.244T>G (p.Cys82Gly)

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.244T>G (p.Cys82Gly)
HGVS:
  • NC_000019.10:g.11102717T>G
  • NG_009060.1:g.18337T>G
  • NM_000527.5:c.244T>GMANE SELECT
  • NM_001195798.2:c.244T>G
  • NM_001195799.2:c.190+2372T>G
  • NM_001195800.2:c.244T>G
  • NM_001195803.2:c.244T>G
  • NP_000518.1:p.Cys82Gly
  • NP_000518.1:p.Cys82Gly
  • NP_001182727.1:p.Cys82Gly
  • NP_001182729.1:p.Cys82Gly
  • NP_001182732.1:p.Cys82Gly
  • LRG_274t1:c.244T>G
  • LRG_274:g.18337T>G
  • LRG_274p1:p.Cys82Gly
  • NC_000019.9:g.11213393T>G
  • NM_000527.4:c.244T>G
  • c.244T>G
Protein change:
C82G
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001652; dbSNP: rs879254447
NCBI 1000 Genomes Browser:
rs879254447
Molecular consequence:
  • NM_001195799.2:c.190+2372T>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.244T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.244T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.244T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.244T>G - 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
SCV002174214Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Dec 4, 2021)
germlineclinical testing

PubMed (7)
[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

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 Invitae, SCV002174214.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys82 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 251091). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 20809525, 28964736). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 82 of the LDLR protein (p.Cys82Gly).

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

Last Updated: Sep 1, 2024