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NM_000527.5(LDLR):c.763T>G (p.Cys255Gly) AND Hypercholesterolemia, familial, 1

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Oct 6, 2023
Review status:
criteria provided, conflicting classifications
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:
RCV000237434.3

Allele description [Variation Report for NM_000527.5(LDLR):c.763T>G (p.Cys255Gly)]

NM_000527.5(LDLR):c.763T>G (p.Cys255Gly)

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.763T>G (p.Cys255Gly)
HGVS:
  • NC_000019.10:g.11106633T>G
  • NG_009060.1:g.22253T>G
  • NM_000527.5:c.763T>GMANE SELECT
  • NM_001195798.2:c.763T>G
  • NM_001195799.2:c.640T>G
  • NM_001195800.2:c.314-759T>G
  • NM_001195803.2:c.382T>G
  • NP_000518.1:p.Cys255Gly
  • NP_001182727.1:p.Cys255Gly
  • NP_001182728.1:p.Cys214Gly
  • NP_001182732.1:p.Cys128Gly
  • LRG_274:g.22253T>G
  • NC_000019.9:g.11217309T>G
  • c.763T>G
Protein change:
C128G
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000114; dbSNP: rs879254668
NCBI 1000 Genomes Browser:
rs879254668
Molecular consequence:
  • NM_001195800.2:c.314-759T>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.763T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.763T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.640T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.382T>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Hypercholesterolemia, familial, 1
Synonyms:
LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000294960LDLR-LOVD, British Heart Foundation
criteria provided, single submitter

(ACGS Guidelines, 2013)		Likely pathogenic
(Mar 25, 2016) 		germlineliterature only

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

Citation Link,

SCV004837567All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Oct 6, 2023) 		germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot provided1not providedliterature only
not providedgermlineunknown1not providednot provided108544not providedclinical testing

Citations

PubMed

The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein.

Hobbs HH, Russell DW, Brown MS, Goldstein JL.

Annu Rev Genet. 1990;24:133-70. Review. No abstract available.

PubMed [citation]
PMID:
2088165

The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA.

Yamamoto T, Davis CG, Brown MS, Schneider WJ, Casey ML, Goldstein JL, Russell DW.

Cell. 1984 Nov;39(1):27-38.

PubMed [citation]
PMID:
6091915
See all PubMed Citations (8)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294960.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedliterature only PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

From All of Us Research Program, National Institutes of Health, SCV004837567.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (8)

Description

This missense variant replaces cysteine with glycine at codon 255 of the LDLR protein. This variant is also known as p.Cys234Gly in the mature protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15823276, 16250003, 23833242, 32770674). In several of these instances, this variant has been reported to occur in cis or in unknown phase with p.Gln254His (PMID: 15823276, 23833242, 32770674). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided1not providednot providednot provided

Last Updated: May 7, 2024