NM_000527.5(LDLR):c.427T>A (p.Cys143Ser) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 23, 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:: RCV004033034.1

Allele description [Variation Report for NM_000527.5(LDLR):c.427T>A (p.Cys143Ser)]

NM_000527.5(LDLR):c.427T>A (p.Cys143Ser)

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.427T>A (p.Cys143Ser)

HGVS:

NC_000019.10:g.11105333T>A
NG_009060.1:g.20953T>A
NM_000527.5:c.427T>AMANE SELECT
NM_001195798.2:c.427T>A
NM_001195799.2:c.304T>A
NM_001195800.2:c.314-2059T>A
NM_001195803.2:c.314-1232T>A
NP_000518.1:p.Cys143Ser
NP_001182727.1:p.Cys143Ser
NP_001182728.1:p.Cys102Ser
LRG_274t1:c.427T>A
LRG_274:g.20953T>A
NC_000019.9:g.11216009T>A
NC_000019.9:g.11216009T>A
NM_000527.4:c.427T>A

Protein change:

C102S

Links:

dbSNP: rs875989901

NCBI 1000 Genomes Browser:

rs875989901

Molecular consequence:

NM_001195800.2:c.314-2059T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1232T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.427T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.427T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.304T>A - 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
SCV003967591	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (May 23, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12124988, 27765764, 28964736, 29399563, 34040191 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003967591

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(May 23, 2023)

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 UMD-LDLR database: additions to the software and 490 new entries to the database.

Villéger L, Abifadel M, Allard D, Rabès JP, Thiart R, Kotze MJ, Béroud C, Junien C, Boileau C, Varret M.

Hum Mutat. 2002 Aug;20(2):81-7. Review.

PubMed [citation]

PMID:: 12124988

Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically.

Wang J, Dron JS, Ban MR, Robinson JF, McIntyre AD, Alazzam M, Zhao PJ, Dilliott AA, Cao H, Huff MW, Rhainds D, Low-Kam C, Dubé MP, Lettre G, Tardif JC, Hegele RA.

Arterioscler Thromb Vasc Biol. 2016 Dec;36(12):2439-2445. Epub 2016 Oct 20.

PubMed [citation]

PMID:: 27765764

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV003967591.2

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

Description

The c.427T>A (p.C143S) alteration is located in exon 4 (coding exon 4) of the LDLR gene. This alteration results from a T to A substitution at nucleotide position 427, causing the cysteine (C) at amino acid position 143 to be replaced by a serine (S). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in individuals reported to have familial hypercholesterolemia (FH) (Defesche, 2017; Wang, 2016; Ajufo, 2021). Another alteration at the same codon, c.428G>A (p.C143Y), has also been reported in association with FH (Kim, 2018). This amino acid position is highly conserved in available vertebrate species. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in FH (Villéger, 2002). Internal structural analysis indicates this variant eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 3domain (Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as 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: Nov 3, 2024

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