NM_000527.5(LDLR):c.1574A>T (p.Asp525Val) AND Familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 7, 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:: RCV003581628.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1574A>T (p.Asp525Val)]

NM_000527.5(LDLR):c.1574A>T (p.Asp525Val)

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.1574A>T (p.Asp525Val)

HGVS:

NC_000019.10:g.11113750A>T
NG_009060.1:g.29370A>T
NM_000527.5:c.1574A>TMANE SELECT
NM_001195798.2:c.1574A>T
NM_001195799.2:c.1451A>T
NM_001195800.2:c.1070A>T
NM_001195803.2:c.1193A>T
NP_000518.1:p.Asp525Val
NP_000518.1:p.Asp525Val
NP_001182727.1:p.Asp525Val
NP_001182728.1:p.Asp484Val
NP_001182729.1:p.Asp357Val
NP_001182732.1:p.Asp398Val
LRG_274t1:c.1574A>T
LRG_274:g.29370A>T
LRG_274p1:p.Asp525Val
NC_000019.9:g.11224426A>T
NM_000527.4:c.1574A>T
c.1574A>T
p.(Asp525Val)

Protein change:

D357V

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000739; dbSNP: rs879254943

NCBI 1000 Genomes Browser:

rs879254943

Molecular consequence:

NM_000527.5:c.1574A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1574A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1451A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1070A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1193A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004298363	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 7, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15556094, 16389549, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004298363

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 7, 2023)

germline

clinical testing

PubMed (3)
[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

Genetic screening of patients with familial hypercholesterolaemia (FH): a New Zealand perspective.

Laurie AD, Scott RS, George PM.

Atheroscler Suppl. 2004 Dec;5(5):13-5.

PubMed [citation]

PMID:: 15556094

Mutational analysis in UK patients with a clinical diagnosis of familial hypercholesterolaemia: relationship with plasma lipid traits, heart disease risk and utility in relative tracing.

Humphries SE, Cranston T, Allen M, Middleton-Price H, Fernandez MC, Senior V, Hawe E, Iversen A, Wray R, Crook MA, Wierzbicki AS.

J Mol Med (Berl). 2006 Mar;84(3):203-14. Epub 2005 Dec 31.

PubMed [citation]

PMID:: 16389549

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004298363.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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: 251902). This variant is also known as c.1573A>T (p.D504V). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 15556094, 16389549). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 525 of the LDLR protein (p.Asp525Val).

#	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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