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NM_000527.5(LDLR):c.298G>A (p.Asp100Asn) AND Cardiovascular phenotype

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Dec 23, 2021
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV002436073.2

Allele description [Variation Report for NM_000527.5(LDLR):c.298G>A (p.Asp100Asn)]

NM_000527.5(LDLR):c.298G>A (p.Asp100Asn)

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.298G>A (p.Asp100Asn)
Other names:
NM_000527.5(LDLR):c.298G>A
HGVS:
  • NC_000019.10:g.11102771G>A
  • NG_009060.1:g.18391G>A
  • NM_000527.5:c.298G>AMANE SELECT
  • NM_001195798.2:c.298G>A
  • NM_001195799.2:c.190+2426G>A
  • NM_001195800.2:c.298G>A
  • NM_001195803.2:c.298G>A
  • NP_000518.1:p.Asp100Asn
  • NP_000518.1:p.Asp100Asn
  • NP_001182727.1:p.Asp100Asn
  • NP_001182729.1:p.Asp100Asn
  • NP_001182732.1:p.Asp100Asn
  • LRG_274t1:c.298G>A
  • LRG_274:g.18391G>A
  • LRG_274p1:p.Asp100Asn
  • NC_000019.9:g.11213447G>A
  • NM_000527.4:c.298G>A
  • c.298G>A
Protein change:
D100N
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001686; dbSNP: rs879254459
NCBI 1000 Genomes Browser:
rs879254459
Molecular consequence:
  • NM_001195799.2:c.190+2426G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.298G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.298G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.298G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.298G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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    Anemia, Aplastic
    A form of anemia in which the bone marrow fails to produce adequate numbers of peripheral blood elements.<br/>
    MeSH
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    Hemophilia B
    A deficiency of blood coagulation factor IX inherited as an X-linked disorder. (Also known as Christmas Disease, after the first patient studied in detail, not the holy day.) ...<br/>Year introduced: 1999(1966)
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    Factor XII Deficiency
    An absence or reduced level of blood coagulation factor XII. It normally occurs in the absence of patient or family history of hemorrhagic disorders and is marked by prolonged...<br/>Year introduced: 1978
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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002751463Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Dec 23, 2021) 		germlineclinical testing

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

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program.

Leren TP, Manshaus T, Skovholt U, Skodje T, Nossen IE, Teie C, Sørensen S, Bakken KS.

Semin Vasc Med. 2004 Feb;4(1):75-85. Review.

PubMed [citation]
PMID:
15199436

Rare intracranial cholesterol deposition and a homozygous mutation of LDLR in a familial hypercholesterolemia patient.

Li H, Zhang Y, Wei X, Peng Y, Yang P, Tan H, Chen C, Pan Q, Liang D, Wu L.

Gene. 2015 Sep 15;569(2):313-7. doi: 10.1016/j.gene.2015.04.071. Epub 2015 Apr 29.

PubMed [citation]
PMID:
25936346
See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV002751463.2

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

Description

The p.D100N variant (also known as c.298G>A and legacy p.D79N), located in coding exon 3 of the LDLR gene, results from a G to A substitution at nucleotide position 298. The aspartic acid at codon 100 is replaced by asparagine, an amino acid with highly similar properties. This variant has been reported in multiple individuals with hypercholesterolemia, including at least two homozygous cases (Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Li H et al. Gene, 2015 Sep;569:313-7; Hu M et al. J. Atheroscler. Thromb., 2016 May;23:520-31; Moss S et al. Cardiovasc Revasc Med, 2018 12;19:20-22; Hsiung YC et al. Atherosclerosis, 2018 10;277:440-447). Based on internal structural analysis, this variant is deleterious, impacting a residue in the conserved cluster of acidic amino acids at the C-terminal end of LDLR class A repeat 2 (Ambry internal data; Jeon H and Blacklow C. Annu. Rev. Biochem. 2005;74:535-62). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

Last Updated: Sep 29, 2024