NM_000527.5(LDLR):c.2242G>A (p.Asp748Asn) AND Familial hypercholesterolemia 1

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(2) (Last evaluated: Aug 22, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000237615.6

Allele description [Variation Report for NM_000527.5(LDLR):c.2242G>A (p.Asp748Asn)]

NM_000527.5(LDLR):c.2242G>A (p.Asp748Asn)

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.2242G>A (p.Asp748Asn)
Other names:
NP_000518.1:p.D748N
HGVS:
  • NC_000019.10:g.11123275G>A
  • NG_009060.1:g.38895G>A
  • NM_000527.4:c.2242G>A
  • NM_000527.5:c.2242G>AMANE SELECT
  • NM_001195798.2:c.2242G>A
  • NM_001195799.2:c.2119G>A
  • NM_001195800.2:c.1738G>A
  • NM_001195803.2:c.1708G>A
  • NP_000518.1:p.Asp748Asn
  • NP_000518.1:p.Asp748Asn
  • NP_001182727.1:p.Asp748Asn
  • NP_001182728.1:p.Asp707Asn
  • NP_001182729.1:p.Asp580Asn
  • NP_001182732.1:p.Asp570Asn
  • LRG_274t1:c.2242G>A
  • LRG_274:g.38895G>A
  • LRG_274p1:p.Asp748Asn
  • NC_000019.9:g.11233951G>A
  • c.2242G>A
Protein change:
D570N
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000290; dbSNP: rs150104358
NCBI 1000 Genomes Browser:
rs150104358
Molecular consequence:
  • NM_000527.4:c.2242G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000527.5:c.2242G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.2242G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.2119G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.1738G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.1708G>A - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
unknown functional consequence - Comment(s)
Observations:
2

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
SCV000295925LDLR-LOVD, British Heart Foundationcriteria provided, single submitter
Likely benign
(Mar 25, 2016)
germlineliterature only

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

Citation Link,

SCV000410544Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Uncertain significance
(Jan 13, 2018)
germlineclinical testing

Citation Link,

SCV000484755Robarts Research Institute,Western Universitycriteria provided, single submitter
Uncertain significance
(Aug 22, 2019)
germlineclinical testing

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

SCV000606618Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrumno assertion criteria providedPathogenicgermlineresearch

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes2not providednot provided1not providedclinical testing, literature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, research

Citations

PubMed

Low-density lipoprotein receptor gene familial hypercholesterolemia variant database: update and pathological assessment.

Usifo E, Leigh SE, Whittall RA, Lench N, Taylor A, Yeats C, Orengo CA, Martin AC, Celli J, Humphries SE.

Ann Hum Genet. 2012 Sep;76(5):387-401. doi: 10.1111/j.1469-1809.2012.00724.x.

PubMed [citation]
PMID:
22881376

Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically.

Wang J, Dron JS, Ban MR, Robinson JF, McIntyre AD, Alazzam M, Zhao PJ, Dilliott AA, Cao H, Huff MW, Rhainds D, Low-Kam C, Dubé MP, Lettre G, Tardif JC, Hegele RA.

Arterioscler Thromb Vasc Biol. 2016 Dec;36(12):2439-2445. Epub 2016 Oct 20.

PubMed [citation]
PMID:
27765764

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295925.2

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

From Illumina Clinical Services Laboratory,Illumina, SCV000410544.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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

From Robarts Research Institute,Western University, SCV000484755.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum, SCV000606618.1

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

Last Updated: Oct 8, 2021

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