NM_000527.5(LDLR):c.1723C>T (p.Leu575Phe) AND Cardiovascular phenotype

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 7, 2022
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:: RCV003159635.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1723C>T (p.Leu575Phe)]

NM_000527.5(LDLR):c.1723C>T (p.Leu575Phe)

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.1723C>T (p.Leu575Phe)

HGVS:

NC_000019.10:g.11116876C>T
NG_009060.1:g.32496C>T
NM_000527.5:c.1723C>TMANE SELECT
NM_001195798.2:c.1723C>T
NM_001195799.2:c.1600C>T
NM_001195800.2:c.1219C>T
NM_001195803.2:c.1342C>T
NP_000518.1:p.Leu575Phe
NP_000518.1:p.Leu575Phe
NP_001182727.1:p.Leu575Phe
NP_001182728.1:p.Leu534Phe
NP_001182729.1:p.Leu407Phe
NP_001182732.1:p.Leu448Phe
LRG_274t1:c.1723C>T
LRG_274:g.32496C>T
LRG_274p1:p.Leu575Phe
NC_000019.9:g.11227552C>T
NM_000527.4(LDLR):c.1723C>T
NM_000527.4:c.1723C>T
p.Leu575Phe

Protein change:

L407F

Links:

dbSNP: rs1205480064

NCBI 1000 Genomes Browser:

rs1205480064

Molecular consequence:

NM_000527.5:c.1723C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1723C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1600C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1219C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1342C>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
SCV003912554	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Dec 7, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 27830735, 28502495, 32041611, 33994402, 36325061 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003912554

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Dec 7, 2022)

germline

clinical testing

PubMed (5)
[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 use of targeted exome sequencing in genetic diagnosis of young patients with severe hypercholesterolemia.

Jiang L, Wu WF, Sun LY, Chen PP, Wang W, Benito-Vicente A, Zhang F, Pan XD, Cui W, Yang SW, Zhou YJ, Martin C, Wang LY.

Sci Rep. 2016 Nov 10;6:36823. doi: 10.1038/srep36823.

PubMed [citation]

PMID:: 27830735
PMCID:: PMC5103295

Detection of common sequence variations of familial hypercholesterolemia in Taiwan using DNA mass spectrometry.

Chiou KR, Charng MJ.

J Clin Lipidol. 2017 Mar - Apr;11(2):386-393.e6. doi: 10.1016/j.jacl.2016.12.014. Epub 2017 Jan 10.

PubMed [citation]

PMID:: 28502495

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV003912554.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The p.L575F variant (also known as c.1723C>T), located in coding exon 12 of the LDLR gene, results from a C to T substitution at nucleotide position 1723. The leucine at codon 575 is replaced by phenylalanine, an amino acid with highly similar properties. This variant has been detected in familial hypercholesterolemia (FH) and mixed dyslipidemia cohorts; however, details were limited (Chiou KR et al. J Clin Lipidol, 2017 Jan;11:386-393.e6; Huang CC et al. J Atheroscler Thromb, 2022 May;29:639-653; Dron JS et al. BMC Med Genomics, 2020 Feb;13:23). This variant co-occurred with a second LDLR variant in a homozygous FH cohort; however, details were limited (Jiang L et al. Sci Rep, 2016 Nov;6:36823; Du Z et al. iScience, 2022 Nov;25:105334). Functional studies by one group suggest this variant may result in a moderate reduction in protein function (Jiang L et al. Sci Rep, 2016 Nov;6:36823). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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: Sep 1, 2024

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