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NM_000527.5(LDLR):c.827G>A (p.Cys276Tyr) AND Hypercholesterolemia, familial, 1

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Jan 8, 2024
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:
RCV000237878.3

Allele description [Variation Report for NM_000527.5(LDLR):c.827G>A (p.Cys276Tyr)]

NM_000527.5(LDLR):c.827G>A (p.Cys276Tyr)

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.827G>A (p.Cys276Tyr)
HGVS:
  • NC_000019.10:g.11107401G>A
  • NG_009060.1:g.23021G>A
  • NM_000527.5:c.827G>AMANE SELECT
  • NM_001195798.2:c.827G>A
  • NM_001195799.2:c.704G>A
  • NM_001195800.2:c.323G>A
  • NM_001195803.2:c.446G>A
  • NP_000518.1:p.Cys276Tyr
  • NP_001182727.1:p.Cys276Tyr
  • NP_001182728.1:p.Cys235Tyr
  • NP_001182729.1:p.Cys108Tyr
  • NP_001182732.1:p.Cys149Tyr
  • LRG_274t1:c.827G>A
  • LRG_274:g.23021G>A
  • NC_000019.9:g.11218077G>A
  • NM_000527.4:c.827G>A
  • P01130:p.Cys276Tyr
  • c.827G>A
Protein change:
C108Y
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000619; UniProtKB: P01130#VAR_005349; dbSNP: rs730882089
NCBI 1000 Genomes Browser:
rs730882089
Molecular consequence:
  • NM_000527.5:c.827G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.827G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.704G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.323G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.446G>A - 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
SCV000295003LDLR-LOVD, British Heart Foundation
criteria provided, single submitter

(ACGS Guidelines, 2013)		Likely pathogenic
(Mar 25, 2016) 		germlineresearch

Citation Link,

SCV004839043All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely Pathogenic
(Jan 8, 2024) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot provided1not providedresearch
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 (5)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295003.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedresearchnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

From All of Us Research Program, National Institutes of Health, SCV004839043.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (5)

Description

This missense variant replaces cysteine with tyrosine at codon 276 in the LDLR type A repeat 7 of the LDLR protein. This variant is also known as p.Cys255Tyr 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 observed in compound heterozygous state with a known pathogenic LDLR variant in one individual affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 36229885). Multiple different variants affecting the same codon (p.Cys276Gly, p.Cys276Trp, p.Cys276Arg, p.Cys276Ser), are considered to be disease-causing (ClinVar variation ID: 251480, 251482, 251479, 183096), suggesting that cysteine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.

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

Last Updated: May 7, 2024