NM_000527.5(LDLR):c.1800G>C (p.Glu600Asp) AND Familial hypercholesterolemia 1

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(2) (Last evaluated: Apr 23, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000497106.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1800G>C (p.Glu600Asp)]

NM_000527.5(LDLR):c.1800G>C (p.Glu600Asp)

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.1800G>C (p.Glu600Asp)
HGVS:
  • NC_000019.10:g.11116953G>C
  • NG_009060.1:g.32573G>C
  • NM_000527.4:c.1800G>C
  • NM_000527.5:c.1800G>CMANE SELECT
  • NM_001195798.2:c.1800G>C
  • NM_001195799.2:c.1677G>C
  • NM_001195800.2:c.1296G>C
  • NM_001195803.2:c.1419G>C
  • NP_000518.1:p.Glu600Asp
  • NP_000518.1:p.Glu600Asp
  • NP_001182727.1:p.Glu600Asp
  • NP_001182728.1:p.Glu559Asp
  • NP_001182729.1:p.Glu432Asp
  • NP_001182732.1:p.Glu473Asp
  • LRG_274t1:c.1800G>C
  • LRG_274:g.32573G>C
  • LRG_274p1:p.Glu600Asp
  • NC_000019.9:g.11227629G>C
Protein change:
E432D
Links:
Molecular consequence:
  • NM_000527.4:c.1800G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000527.5:c.1800G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1800G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1677G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.1296G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.1419G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Familial hypercholesterolemia 1 (FHCL1)
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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000588607Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasilcriteria provided, single submitter
Likely pathogenic
(Mar 1, 2016)
germlineresearch

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

SCV000607642Fundacion Hipercolesterolemia Familiar - SAFEHEARTcriteria provided, single submitter
Uncertain significance
(Mar 1, 2016)
germlineresearch

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

SCV000827107Invitaecriteria provided, single submitter
Uncertain significance
(Apr 23, 2018)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Femoral atherosclerosis in heterozygous familial hypercholesterolemia: influence of the genetic defect.

Junyent M, Gilabert R, Zambón D, Pocoví M, Mallén M, Cofán M, Núñez I, Civeira F, Tejedor D, Ros E.

Arterioscler Thromb Vasc Biol. 2008 Mar;28(3):580-6. Epub 2007 Dec 20.

PubMed [citation]
PMID:
18096825
See all PubMed Citations (3)

Details of each submission

From Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil, SCV000588607.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607642.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000827107.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces glutamic acid with aspartic acid at codon 600 of the LDLR protein (p.Glu600Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 18096825). ClinVar contains an entry for this variant (Variation ID: 431535). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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: Oct 25, 2021

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