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NM_000527.5(LDLR):c.523G>A (p.Asp175Asn) AND Cardiovascular phenotype

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 13, 2023
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:
RCV002336075.4

Allele description [Variation Report for NM_000527.5(LDLR):c.523G>A (p.Asp175Asn)]

NM_000527.5(LDLR):c.523G>A (p.Asp175Asn)

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.523G>A (p.Asp175Asn)
Other names:
D154N; FH Afrikaner 3; FH Afrikaner-3
HGVS:
  • NC_000019.10:g.11105429G>A
  • NG_009060.1:g.21049G>A
  • NM_000527.5:c.523G>AMANE SELECT
  • NM_001195798.2:c.523G>A
  • NM_001195799.2:c.400G>A
  • NM_001195800.2:c.314-1963G>A
  • NM_001195803.2:c.314-1136G>A
  • NP_000518.1:p.Asp175Asn
  • NP_000518.1:p.Asp175Asn
  • NP_001182727.1:p.Asp175Asn
  • NP_001182728.1:p.Asp134Asn
  • LRG_274t1:c.523G>A
  • LRG_274:g.21049G>A
  • NC_000019.9:g.11216105G>A
  • NM_000527.4(LDLR):c.523G>A
  • NM_000527.4:c.523G>A
  • P01130:p.Asp175Asn
  • c.523G>A
Protein change:
D134N; ASP154ASN
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001755; UniProtKB: P01130#VAR_005326; OMIM: 606945.0044; dbSNP: rs121908033
NCBI 1000 Genomes Browser:
rs121908033
Molecular consequence:
  • NM_001195800.2:c.314-1963G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001195803.2:c.314-1136G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000527.5:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.523G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.400G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002645016Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Dec 13, 2023) 		germlineclinical testing

PubMed (6)
[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

Low density lipoprotein receptor founder mutations in Afrikaner familial hypercholesterolaemic patients: a comparison of two geographical areas.

Graadt van Roggen F, van der Westhuyzen DR, Marais AD, Gevers W, Coetzee GA.

Hum Genet. 1991 Dec;88(2):204-8.

PubMed [citation]
PMID:
1757095

The molecular basis and diagnosis of familial hypercholesterolaemia in South African Afrikaners.

Kotze MJ, Langenhoven E, Warnich L, du Plessis L, Retief AE.

Ann Hum Genet. 1991 May;55(2):115-21.

PubMed [citation]
PMID:
1952806
See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV002645016.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

The c.523G>A (p.D175N) alteration is located in exon 4 (coding exon 4) of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 523, causing the aspartic acid (D) at amino acid position 175 to be replaced by an asparagine (N). Based on data from gnomAD, the A allele has an overall frequency of 0.001% (2/251312) total alleles studied. The highest observed frequency was 0.011% (2/18386) of East Asian alleles. This mutation has been found to be a common pathogenic alteration in different South African hypercholesterolemia population cohorts (Kotze, 1989; Kotze, 1991; Graadt van Roggen, 1991), with haplotype analysis indicating that it is a founder mutation (Loubser, 1999). This amino acid position is highly conserved in available vertebrate species. Internal structural analysis indicates that this variant, which impacts a residue in the conserved cluster of acidic amino acids at the C-terminal end of LDLR class A repeat 4, is expected to have a deleterious impact on protein function (Jeon, 2005; Ambry internal data). In vitro functional studies suggest that this alteration (also referred to as p.D154N) causes deficient LDLR function via reduced expression and a decrease in this receptor's affinity for LDL compared to wildtype (Graadt van Roggen, 1995). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.

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

Last Updated: Oct 20, 2024