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NM_000527.5(LDLR):c.904T>G (p.Cys302Gly) AND Familial hypercholesterolemia

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Dec 4, 2018
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:
RCV000808135.3

Allele description [Variation Report for NM_000527.5(LDLR):c.904T>G (p.Cys302Gly)]

NM_000527.5(LDLR):c.904T>G (p.Cys302Gly)

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.904T>G (p.Cys302Gly)
HGVS:
  • NC_000019.10:g.11107478T>G
  • NG_009060.1:g.23098T>G
  • NM_000527.5:c.904T>GMANE SELECT
  • NM_001195798.2:c.904T>G
  • NM_001195799.2:c.781T>G
  • NM_001195800.2:c.400T>G
  • NM_001195803.2:c.523T>G
  • NP_000518.1:p.Cys302Gly
  • NP_000518.1:p.Cys302Gly
  • NP_001182727.1:p.Cys302Gly
  • NP_001182728.1:p.Cys261Gly
  • NP_001182729.1:p.Cys134Gly
  • NP_001182732.1:p.Cys175Gly
  • LRG_274t1:c.904T>G
  • LRG_274:g.23098T>G
  • LRG_274p1:p.Cys302Gly
  • NC_000019.9:g.11218154T>G
  • NM_000527.4:c.904T>G
Protein change:
C134G
Links:
dbSNP: rs1555803891
NCBI 1000 Genomes Browser:
rs1555803891
Molecular consequence:
  • NM_000527.5:c.904T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.904T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.781T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.400T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.523T>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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000948227Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Dec 4, 2018) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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

Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP).

Krieger M, Herz J.

Annu Rev Biochem. 1994;63:601-37. Review. No abstract available.

PubMed [citation]
PMID:
7979249
See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000948227.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces cysteine with glycine at codon 302 of the LDLR protein (p.Cys302Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with LDLR-related conditions. 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.Cys302 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 26802169, 10206683, 9026534, 23833242), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Sep 29, 2024