NM_000527.5(LDLR):c.1735G>A (p.Asp579Asn) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 20, 2022
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:: RCV002229692.6

Allele description [Variation Report for NM_000527.5(LDLR):c.1735G>A (p.Asp579Asn)]

NM_000527.5(LDLR):c.1735G>A (p.Asp579Asn)

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.1735G>A (p.Asp579Asn)

Other names:

FH Cincinnati-4

HGVS:

NC_000019.10:g.11116888G>A
NG_009060.1:g.32508G>A
NM_000527.5:c.1735G>AMANE SELECT
NM_001195798.2:c.1735G>A
NM_001195799.2:c.1612G>A
NM_001195800.2:c.1231G>A
NM_001195803.2:c.1354G>A
NP_000518.1:p.Asp579Asn
NP_000518.1:p.Asp579Asn
NP_001182727.1:p.Asp579Asn
NP_001182728.1:p.Asp538Asn
NP_001182729.1:p.Asp411Asn
NP_001182732.1:p.Asp452Asn
LRG_274t1:c.1735G>A
LRG_274:g.32508G>A
LRG_274p1:p.Asp579Asn
NC_000019.9:g.11227564G>A
NM_000527.4:c.1735G>A
P01130:p.Asp579Asn
c.1735G>A

Protein change:

D411N

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001510; UniProtKB: P01130#VAR_005402; dbSNP: rs875989929

NCBI 1000 Genomes Browser:

rs875989929

Molecular consequence:

NM_000527.5:c.1735G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1735G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1612G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1231G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1354G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

Recent activity

Clear Turn Off Turn On

Taxonomy Links for Nucleotide (Select 1932143159) (1)
Taxonomy

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000544674	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 20, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10978268, 23375686, 1301956, 16542394, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000544674

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 20, 2022)

germline

clinical testing

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

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

Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype.

Bertolini S, Cantafora A, Averna M, Cortese C, Motti C, Martini S, Pes G, Postiglione A, Stefanutti C, Blotta I, Pisciotta L, Rolleri M, Langheim S, Ghisellini M, Rabbone I, Calandra S.

Arterioscler Thromb Vasc Biol. 2000 Sep;20(9):E41-52.

PubMed [citation]

PMID:: 10978268

Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy.

Bertolini S, Pisciotta L, Rabacchi C, Cefalù AB, Noto D, Fasano T, Signori A, Fresa R, Averna M, Calandra S.

Atherosclerosis. 2013 Apr;227(2):342-8. doi: 10.1016/j.atherosclerosis.2013.01.007. Epub 2013 Jan 19.

PubMed [citation]

PMID:: 23375686

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000544674.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp558 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10978268, 23375686). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 252006). This variant is also known as p.Asp558Asn. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 16542394). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 579 of the LDLR protein (p.Asp579Asn).

#	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

ClinVar

Relating variation to medicine