NM_000527.5(LDLR):c.1721G>A (p.Arg574His) AND Hypercholesterolemia

Clinical significance:Likely pathogenic (Last evaluated: Feb 11, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001256078.1

Allele description [Variation Report for NM_000527.5(LDLR):c.1721G>A (p.Arg574His)]

NM_000527.5(LDLR):c.1721G>A (p.Arg574His)

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.1721G>A (p.Arg574His)
HGVS:
  • NC_000019.10:g.11116874G>A
  • NG_009060.1:g.32494G>A
  • NM_000527.4:c.1721G>A
  • NM_000527.5:c.1721G>AMANE SELECT
  • NM_001195798.2:c.1721G>A
  • NM_001195799.2:c.1598G>A
  • NM_001195800.2:c.1217G>A
  • NM_001195803.2:c.1340G>A
  • NP_000518.1:p.Arg574His
  • NP_000518.1:p.Arg574His
  • NP_001182727.1:p.Arg574His
  • NP_001182728.1:p.Arg533His
  • NP_001182729.1:p.Arg406His
  • NP_001182732.1:p.Arg447His
  • LRG_274t1:c.1721G>A
  • LRG_274:g.32494G>A
  • LRG_274p1:p.Arg574His
  • NC_000019.9:g.11227550G>A
  • P01130:p.Arg574His
  • c.1721G>A
Protein change:
R406H
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000233; UniProtKB: P01130#VAR_072852
Molecular consequence:
  • NM_000527.4:c.1721G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000527.5:c.1721G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1721G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1598G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.1217G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.1340G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Hypercholesterolemia
Synonyms:
Elevated serum cholesterol; Elevated total cholesterol; Increased total cholesterol; See all synonyms [MedGen]
Identifiers:
MedGen: C1522133; Human Phenotype Ontology: HP:0003124

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001432865New York Genome Center - CSER-NYCKidSeqcriteria provided, single submitter
Likely pathogenic
(Feb 11, 2020)
maternalclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedmaternalno1not providednot provided1not providedclinical testing

Citations

PubMed

Pseudoxanthoma elasticum and familial hypercholesterolemia: a deleterious combination of cardiovascular risk factors.

Pisciotta L, Tarugi P, Borrini C, Bellocchio A, Fresa R, Guerra D, Quaglino D, Ronchetti I, Calandra S, Bertolini S.

Atherosclerosis. 2010 May;210(1):173-6. doi: 10.1016/j.atherosclerosis.2009.11.028. Epub 2009 Nov 24.

PubMed [citation]
PMID:
20018285

Familial hypercholesterolemia in Brazil: cascade screening program, clinical and genetic aspects.

Jannes CE, Santos RD, de Souza Silva PR, Turolla L, Gagliardi AC, Marsiglia JD, Chacra AP, Miname MH, Rocha VZ, Filho WS, Krieger JE, Pereira AC.

Atherosclerosis. 2015 Jan;238(1):101-7. doi: 10.1016/j.atherosclerosis.2014.11.009. Epub 2014 Nov 14.

PubMed [citation]
PMID:
25461735
See all PubMed Citations (3)

Details of each submission

From New York Genome Center - CSER-NYCKidSeq, SCV001432865.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (3)

Description

The c.1721G>A, p.Arg574His variant in the LDLR gene has been observed in individuals affected with familial hypercholesterolemia [PMID: 20018285; PMID: 25461735; PMID: 23375686]. The variant has 0.0031% allele frequency in the gnomAD database (9 out of 282,858 heterozygous alleles), indicating this is a rare allele. In silico tools predict that this variant is likely to be disruptive[https://useast.ensembl.org/info/docs/tools/vep/index.html]. Variants that disrupt the p.Arg574 amino acid residue in LDLR have been observed in individuals affected with familial hypercholesterolemia [PMID: 20018285; PMID: 25461735; PMCID: PMC4766367; PMID: 19446849; PMID: 11462246]. This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. Based on the available evidence, the c.1721G>A, p.Arg574His variant in the LDLR gene is classified as likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1maternalno1not providednot provided1not providednot providednot provided

Last Updated: May 10, 2021

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