NM_000527.5(LDLR):c.268G>A (p.Asp90Asn) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 4, 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:: RCV002450742.3

Allele description [Variation Report for NM_000527.5(LDLR):c.268G>A (p.Asp90Asn)]

NM_000527.5(LDLR):c.268G>A (p.Asp90Asn)

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.268G>A (p.Asp90Asn)

Other names:

NP_000518.1:p.D90N; NM_000527.5(LDLR):c.268G>A

HGVS:

NC_000019.10:g.11102741G>A
NG_009060.1:g.18361G>A
NM_000527.5:c.268G>AMANE SELECT
NM_001195798.2:c.268G>A
NM_001195799.2:c.190+2396G>A
NM_001195800.2:c.268G>A
NM_001195803.2:c.268G>A
NP_000518.1:p.Asp90Asn
NP_000518.1:p.Asp90Asn
NP_001182727.1:p.Asp90Asn
NP_001182729.1:p.Asp90Asn
NP_001182732.1:p.Asp90Asn
LRG_274t1:c.268G>A
LRG_274:g.18361G>A
LRG_274p1:p.Asp90Asn
NC_000019.9:g.11213417G>A
NM_000527.4:c.268G>A
P01130:p.Asp90Asn
c.268G>A

Protein change:

D90N

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000041; UniProtKB: P01130#VAR_005311; dbSNP: rs749038326

NCBI 1000 Genomes Browser:

rs749038326

Molecular consequence:

NM_001195799.2:c.190+2396G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.268G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.268G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.268G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.268G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002739771	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (May 4, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 1301956, 8347689, 9259195, 9763532, 10933493, 11005141, 12837857, 16250003, 19026292, 20809525, 24956927 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002739771

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(May 4, 2023)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.

Hobbs HH, Brown MS, Goldstein JL.

Hum Mutat. 1992;1(6):445-66. Review.

PubMed [citation]

PMID:: 1301956

Identification of two new LDL-receptor mutations causing homozygous familial hypercholesterolemia in a South African of Indian origin.

Rubinsztein DC, Jialal I, Leitersdorf E, Coetzee GA, van der Westhuyzen DR.

Biochim Biophys Acta. 1993 Aug 4;1182(1):75-82.

PubMed [citation]

PMID:: 8347689

See all PubMed Citations (11)

Details of each submission

From Ambry Genetics, SCV002739771.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

The c.268G>A (p.D90N) alteration is located in exon 3 (coding exon 3) of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 268, causing the aspartic acid (D) at amino acid position 90 to be replaced by an asparagine (N). Based on data from gnomAD, the A allele has an overall frequency of 0.006% (17/282878) total alleles studied. The highest observed frequency was 0.08% (16/19952) of East Asian alleles. This alteration, also known as p.D69N, has been reported in multiple individuals with familial hypercholesterolemia (FH) and in FH cohorts from a variety of ethnic backgrounds (Day, 1997; Mak, 1998; Khoo, 2000; Chang, 2003; Fouchier, 2005; Norsworthy, 2014). Other amino acid substitutions at this position have also been reported in individuals with FH, including D90A (Kolansky, 2008), D90E (Marduel, 2010), D90G (Hobbs, 1992), and D90Y (Rubinsztein, 1993). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this alteration occurs in a known motif in a region of known function with an effect that matches known phenotype (Kurniawan, 2000). The results of functional studies demonstrated that protein product is retained in the endoplasmic reticulum and enzyme activity is reduced (Chang, 2003). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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