NM_000527.5(LDLR):c.1502C>T (p.Ala501Val) AND Cardiovascular phenotype

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Apr 8, 2021
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:: RCV002392745.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1502C>T (p.Ala501Val)]

NM_000527.5(LDLR):c.1502C>T (p.Ala501Val)

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.1502C>T (p.Ala501Val)

HGVS:

NC_000019.10:g.11113678C>T
NG_009060.1:g.29298C>T
NM_000527.5:c.1502C>TMANE SELECT
NM_001195798.2:c.1502C>T
NM_001195799.2:c.1379C>T
NM_001195800.2:c.998C>T
NM_001195803.2:c.1121C>T
NP_000518.1:p.Ala501Val
NP_000518.1:p.Ala501Val
NP_001182727.1:p.Ala501Val
NP_001182728.1:p.Ala460Val
NP_001182729.1:p.Ala333Val
NP_001182732.1:p.Ala374Val
LRG_274t1:c.1502C>T
LRG_274:g.29298C>T
LRG_274p1:p.Ala501Val
NC_000019.9:g.11224354C>T
NM_000527.4:c.1502C>T
c.1502C>T

Protein change:

A333V

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000899; dbSNP: rs755667663

NCBI 1000 Genomes Browser:

rs755667663

Molecular consequence:

NM_000527.5:c.1502C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1502C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1379C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.998C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1121C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002699418	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Apr 8, 2021)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 15823288, 16542394, 23375686, 25014035, 25487149, 27050191, 28932795, 31491741, 33418990, 33533259 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002699418

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Apr 8, 2021)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

Citation Link

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

The relationship of molecular genetic to clinical diagnosis of familial hypercholesterolemia in a Danish population.

Damgaard D, Larsen ML, Nissen PH, Jensen JM, Jensen HK, Soerensen VR, Jensen LG, Faergeman O.

Atherosclerosis. 2005 May;180(1):155-60. Epub 2005 Jan 12.

PubMed [citation]

PMID:: 15823288

Molecular genetic analysis of 1053 Danish individuals with clinical signs of familial hypercholesterolemia.

Brusgaard K, Jordan P, Hansen H, Hansen AB, Hørder M.

Clin Genet. 2006 Mar;69(3):277-83.

PubMed [citation]

PMID:: 16542394

See all PubMed Citations (10)

Details of each submission

From Ambry Genetics, SCV002699418.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

The p.A501V variant (also known as c.1502C>T), located in coding exon 10 of the LDLR gene, results from a C to T substitution at nucleotide position 1502. The alanine at codon 501 is replaced by valine, an amino acid with similar properties, and is located in the EGF precursor-like domain. This alteration, historically described as p.A480V, was detected along with a truncating LDLR alteration in a child with clinical homozygous familial hypercholesterolemia (FH) (Mabuchi H et al. Atherosclerosis, 2014 Sep;236:54-61). This variant has also been reported in multiple individuals with FH from a variety of ethnic backgrounds, as well as in myocardial infarction and coronary artery disease study cohorts; however, specific clinical details were limited (Damgaard D et al. Atherosclerosis, 2005 May;180:155-60; Brusgaard K et al. Clin. Genet., 2006 Mar;69:277-83; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Hori M et al. Atherosclerosis, 2019 10;289:101-108; Meshkov A et al. Genes (Basel), 2021 Jan;12:[Epub ahead of print]). This allele was reported in two heterozygous individuals in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species; however, valine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be 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: Oct 20, 2024

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