NM_000527.5(LDLR):c.902A>T (p.Asp301Val) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 22, 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:: RCV003838013.1

Allele description [Variation Report for NM_000527.5(LDLR):c.902A>T (p.Asp301Val)]

NM_000527.5(LDLR):c.902A>T (p.Asp301Val)

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.902A>T (p.Asp301Val)

HGVS:

NC_000019.10:g.11107476A>T
NG_009060.1:g.23096A>T
NM_000527.5:c.902A>TMANE SELECT
NM_001195798.2:c.902A>T
NM_001195799.2:c.779A>T
NM_001195800.2:c.398A>T
NM_001195803.2:c.521A>T
NP_000518.1:p.Asp301Val
NP_000518.1:p.Asp301Val
NP_001182727.1:p.Asp301Val
NP_001182728.1:p.Asp260Val
NP_001182729.1:p.Asp133Val
NP_001182732.1:p.Asp174Val
LRG_274t1:c.902A>T
LRG_274:g.23096A>T
LRG_274p1:p.Asp301Val
NC_000019.9:g.11218152A>T
NM_000527.4:c.902A>T

Protein change:

D133V

Molecular consequence:

NM_000527.5:c.902A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.902A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.779A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.398A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.521A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia (FH)
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
SCV004632545	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 22, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 30241732, 11600564, 16250003, 25461735, 25463123, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004632545

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 22, 2023)

germline

clinical testing

PubMed (6)
[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

Oligogenic familial hypercholesterolemia, LDL cholesterol, and coronary artery disease.

Tada H, Kawashiri MA, Nomura A, Teramoto R, Hosomichi K, Nohara A, Inazu A, Mabuchi H, Tajima A, Yamagishi M.

J Clin Lipidol. 2018 Nov - Dec;12(6):1436-1444. doi: 10.1016/j.jacl.2018.08.006. Epub 2018 Aug 23.

PubMed [citation]

PMID:: 30241732

Genetic diagnosis of familial hypercholesterolemia in a South European outbreed population: influence of low-density lipoprotein (LDL) receptor gene mutations on treatment response to simvastatin in total, LDL, and high-density lipoprotein cholesterol.

Chaves FJ, Real JT, García-García AB, Civera M, Armengod ME, Ascaso JF, Carmena R.

J Clin Endocrinol Metab. 2001 Oct;86(10):4926-32.

PubMed [citation]

PMID:: 11600564

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV004632545.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 301 of the LDLR protein (p.Asp301Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 30241732; Invitae). This variant is also known as p.Asp280Val. 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 with a positive predictive value of 95%. This variant disrupts the p.Asp301 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11600564, 16250003, 25461735, 25463123; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been 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: Mar 5, 2024

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