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:: RCV001068840.7

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 (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
SCV001233973	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 28, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26802169, 18701038, 27830735, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001233973

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 28, 2019)

germline

clinical testing

PubMed (4)
[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

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 Invitae, SCV001233973.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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.

#	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: Feb 20, 2024

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