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NM_000527.5(LDLR):c.1439C>T (p.Ala480Val) AND Familial hypercholesterolemia

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Nov 28, 2019
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:
RCV001068840.8

Allele description [Variation Report for NM_000527.5(LDLR):c.1439C>T (p.Ala480Val)]

NM_000527.5(LDLR):c.1439C>T (p.Ala480Val)

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.1439C>T (p.Ala480Val)
HGVS:
  • NC_000019.10:g.11113615C>T
  • NG_009060.1:g.29235C>T
  • NM_000527.5:c.1439C>TMANE SELECT
  • NM_001195798.2:c.1439C>T
  • NM_001195799.2:c.1316C>T
  • NM_001195800.2:c.935C>T
  • NM_001195803.2:c.1058C>T
  • NP_000518.1:p.Ala480Val
  • NP_000518.1:p.Ala480Val
  • NP_001182727.1:p.Ala480Val
  • NP_001182728.1:p.Ala439Val
  • NP_001182729.1:p.Ala312Val
  • NP_001182732.1:p.Ala353Val
  • LRG_274t1:c.1439C>T
  • LRG_274:g.29235C>T
  • LRG_274p1:p.Ala480Val
  • NC_000019.9:g.11224291C>T
  • NM_000527.4:c.1439C>T
Protein change:
A312V
Links:
dbSNP: rs1064794259
NCBI 1000 Genomes Browser:
rs1064794259
Molecular consequence:
  • NM_000527.5:c.1439C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1439C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1316C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.935C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.1058C>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
SCV001233973Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Nov 28, 2019) 		germlineclinical testing

PubMed (4)
[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

Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France.

Wintjens R, Bozon D, Belabbas K, MBou F, Girardet JP, Tounian P, Jolly M, Boccara F, Cohen A, Karsenty A, Dubern B, Carel JC, Azar-Kolakez A, Feillet F, Labarthe F, Gorsky AM, Horovitz A, Tamarindi C, Kieffer P, Lienhardt A, Lascols O, Di Filippo M, et al.

J Lipid Res. 2016 Mar;57(3):482-91. doi: 10.1194/jlr.P055699. Epub 2016 Jan 22.

PubMed [citation]
PMID:
26802169
PMCID:
PMC4766997

Functional analysis of low-density lipoprotein receptor in homozygous familial hypercholesterolemia patients with novel 1439 C-->T mutation of low-density lipoprotein receptor gene.

Lin J, Wang LY, Liu S, Xia JH, Yong Q, Du LP, Pan XD, Xue H, Chen BS, Jiang ZS.

Chin Med J (Engl). 2008 May 5;121(9):776-81.

PubMed [citation]
PMID:
18701038
See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001233973.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala480 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 26802169), which suggests that this may be a clinically significant amino acid residue. 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. This variant has been observed to segregate with familial hypercholesterolemia in a family (PMID: 18701038) and has been observed in individuals affected with this disease (PMID: 27830735, Invitae). This variant is also known as p.Ala459Val in the literature. ClinVar contains an entry for this variant (Variation ID: 420052). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 480 of the LDLR protein (p.Ala480Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine.

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

Last Updated: Sep 29, 2024