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NM_000527.5(LDLR):c.910G>A (p.Asp304Asn) AND Cardiovascular phenotype

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Aug 18, 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:
RCV002371758.9

Allele description [Variation Report for NM_000527.5(LDLR):c.910G>A (p.Asp304Asn)]

NM_000527.5(LDLR):c.910G>A (p.Asp304Asn)

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.910G>A (p.Asp304Asn)
Other names:
D283N; FH Denver 2; NM_000527.5(LDLR):c.910G>A
HGVS:
  • NC_000019.10:g.11107484G>A
  • NG_009060.1:g.23104G>A
  • NM_000527.5:c.910G>AMANE SELECT
  • NM_001195798.2:c.910G>A
  • NM_001195799.2:c.787G>A
  • NM_001195800.2:c.406G>A
  • NM_001195803.2:c.529G>A
  • NP_000518.1:p.Asp304Asn
  • NP_000518.1:p.Asp304Asn
  • NP_001182727.1:p.Asp304Asn
  • NP_001182728.1:p.Asp263Asn
  • NP_001182729.1:p.Asp136Asn
  • NP_001182732.1:p.Asp177Asn
  • LRG_274t1:c.910G>A
  • LRG_274:g.23104G>A
  • LRG_274p1:p.Asp304Asn
  • NC_000019.9:g.11218160G>A
  • NM_000527.4:c.910G>A
  • P01130:p.Asp304Asn
  • c.910G>A
Protein change:
D136N; ASP283ASN
Links:
LDLR-LOVD, British Heart Foundation: LDLR_001861; UniProtKB: P01130#VAR_005355; OMIM: 606945.0008; dbSNP: rs121908030
NCBI 1000 Genomes Browser:
rs121908030
Molecular consequence:
  • NM_000527.5:c.910G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.910G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.787G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.406G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.529G>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
SCV002687018Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Aug 18, 2021) 		germlineclinical testing

PubMed (20)
[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

The molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Defesche JC, Umans-Eckenhausen MW, Kastelein JP.

Hum Genet. 2001 Dec;109(6):602-15. Epub 2001 Nov 9.

PubMed [citation]
PMID:
11810272

Receptor-associated protein facilitates proper folding and maturation of the low-density lipoprotein receptor and its class 2 mutants.

Li Y, Lu W, Schwartz AL, Bu G.

Biochemistry. 2002 Apr 16;41(15):4921-8.

PubMed [citation]
PMID:
11939787
See all PubMed Citations (20)

Details of each submission

From Ambry Genetics, SCV002687018.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (20)

Description

The p.D304N pathogenic mutation (also known as c.910G>A), located in coding exon 6 of the LDLR gene, results from a G to A substitution at nucleotide position 910. The aspartic acid at codon 304 is replaced by asparagine, an amino acid with highly similar properties. This mutation (also referred to as p.D283N and Denver-2) has been reported in numerous familial hypercholesterolemia (FH) cohorts (Callis M et al. Mol. Cell. Probes. 1998;12:149-52; Fouchier SW et al. Hum. Genet. 2001;109:602-15; Amsellem S et al. Hum. Genet. 2002;111:501-10; Tosi I et al. Atherosclerosis. 2007;194:102-11; Al-Khateeb A et al. BMC Med. Genet. 2011;12:40; Ahmad Z et al. Circ Cardiovasc Genet. 2012;5:666-75). It has also been described in the homozygous state in an individual whose LDL receptor activity was 5-15% of normal activity and in the compound heterozygous state with the likely pathogenic alteration LDLR p.E101K in an individual with homozygous FH (Bilheimer DW et al. Am. J. Med. Genet. 1985;22:593-8; Khoo KL et al. J Clin Lipidol. 2016;10:1188-94). Functional studies suggest this mutation results in defective transport of the LDLR protein (Hobbs HH et al. Hum. Mutat. 1992;1:445-66; Li Y et al. Biochemistry. 2002;41:4921-8). In addition, three other alterations affecting the same codon (p.D304V, p.D304E, and p.D304Y) have been associated with FH (Hobbs HH et al. Hum. Mutat. 1992;1:445-66; Loux N et al. Hum. Mutat. 1992;1:325-32; Lombardi MP et al. Genet. Test. 2006;10:77-84). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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

Last Updated: Nov 3, 2024