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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:
RCV003838013.2

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
Identifiers:
MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004632545Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Oct 22, 2023) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004632545.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

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

Last Updated: Sep 29, 2024