NM_000527.4(LDLR):c.542C>G (p.Pro181Arg) AND not provided

Clinical significance:Uncertain significance (Last evaluated: Mar 15, 2016)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:

Allele description

NM_000527.4(LDLR):c.542C>G (p.Pro181Arg)

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000527.4(LDLR):c.542C>G (p.Pro181Arg)
  • NC_000019.10:g.11105448C>G
  • NG_009060.1:g.21068C>G
  • NM_000527.4:c.542C>G
  • NM_001195800.1:c.314-1944C>G
  • NP_000518.1:p.Pro181Arg
  • LRG_274t1:c.542C>G
  • LRG_274:g.21068C>G
  • LRG_274p1:p.Pro181Arg
  • NC_000019.9:g.11216124C>G
  • c.542C>G
Protein change:
LDLR-LOVD, British Heart Foundation: LDLR_000361; dbSNP: rs557344672
NCBI 1000 Genomes Browser:
Allele Frequency:
Molecular consequence:
  • NM_001195800.1:c.314-1944C>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.4:c.542C>G - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
no known functional consequence - Comment(s)


MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000189534Dept. of Genetics and Pharmacogenomics, Merck Research Labs

See additional submitters

no assertion provided
    not providednot applicablein vitro

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

    SCV000697237Integrated Genetics/Laboratory Corporation of Americacriteria provided, single submitter
    Uncertain significance
    (Mar 15, 2016)
    germlineclinical testing

    PubMed (10)
    [See all records that cite these PMIDs]

    LabCorp Variant Classification Summary - May 2015.docx

    Citation Link


    In vitro functional profiling of LDL-receptor missense alleles identified through large-scale association testing


    Summary from all submissions

    EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
    not providednot applicablenot applicablenot providednot providednot providednot providednot providedin vitro
    not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing



    Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction.

    Thormaehlen AS, Schuberth C, Won HH, Blattmann P, Joggerst-Thomalla B, Theiss S, Asselta R, Duga S, Merlini PA, Ardissino D, Lander ES, Gabriel S, Rader DJ, Peloso GM, Pepperkok R, Kathiresan S, Runz H.

    PLoS Genet. 2015 Feb;11(2):e1004855. doi: 10.1371/journal.pgen.1004855. Erratum in: PLoS Genet. 2015 Mar;11(3):e1005060.

    PubMed [citation]

    The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations.

    Tichý L, Freiberger T, Zapletalová P, Soška V, Ravčuková B, Fajkusová L.

    Atherosclerosis. 2012 Aug;223(2):401-8. doi: 10.1016/j.atherosclerosis.2012.05.014. Epub 2012 May 23.

    PubMed [citation]
    See all PubMed Citations (11)

    Details of each submission

    From Dept. of Genetics and Pharmacogenomics, Merck Research Labs, SCV000189534.1

    #EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
    1not providednot providednot providednot providedin vitro PubMed (1)
    OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
    1not applicablenot applicablenot providednot providednot providednot providednot providednot providednot provided

    From Integrated Genetics/Laboratory Corporation of America, SCV000697237.1

    #EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
    1not providednot providednot providednot providedclinical testing PubMed (10)


    Variant summary: The c.542C>G affects a non-conserved nucleotide, resulting in an amino acid change, Pro to Arg. 3/4 in-silico tools (SNPs&GO not captured here due to low reliability index) predict this variant to be damaging. This variant was found in 7/131378 control chromosomes including the broad and large populations of ExAC at a frequency of 0.0000533, which does not exceed the predicted maximum expected allele frequency for a pathogenic LDLR variant (0.0012508). This variant has been reported in many FH patients/families with both co-segregation of variant with disease as well as lack of co-segregation observed (Garcia-Garcia_ 2001 and Garcia-Garcia _2011). In vitro functional studies showed that variant of interest altered LDLR precursor processing to the mature form, however, the protein activity was normal (Garcia-Garcia _2011) and showed comparable levels of cellular LDL-uptake to wild type (Thormaehlen_2015), suggesting a possible lack of functional effect which needs to be further clarified. Considering all, there is not enough evidence to conclude on either the pathogenicity or neutral effect of this variant. Therefore, this variant has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.

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

    Last Updated: Sep 8, 2018