NM_000527.5(LDLR):c.1327T>C (p.Trp443Arg) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 5, 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:: RCV004035599.1

Allele description [Variation Report for NM_000527.5(LDLR):c.1327T>C (p.Trp443Arg)]

NM_000527.5(LDLR):c.1327T>C (p.Trp443Arg)

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.1327T>C (p.Trp443Arg)

HGVS:

NC_000019.10:g.11113418T>C
NG_009060.1:g.29038T>C
NM_000527.5:c.1327T>CMANE SELECT
NM_001195798.2:c.1327T>C
NM_001195799.2:c.1204T>C
NM_001195800.2:c.823T>C
NM_001195803.2:c.946T>C
NP_000518.1:p.Trp443Arg
NP_001182727.1:p.Trp443Arg
NP_001182728.1:p.Trp402Arg
NP_001182729.1:p.Trp275Arg
NP_001182732.1:p.Trp316Arg
LRG_274t1:c.1327T>C
LRG_274:g.29038T>C
NC_000019.9:g.11224094T>C
NM_000527.4:c.1327T>C

Protein change:

W275R

Links:

dbSNP: rs773566855

NCBI 1000 Genomes Browser:

rs773566855

Molecular consequence:

NM_000527.5:c.1327T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1327T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1204T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.823T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.946T>C - 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
SCV004066478	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jul 5, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 22081141, 28458923, 32423031, 34074024, 36229885 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004066478

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jul 5, 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

Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH.

Lo Surdo P, Bottomley MJ, Calzetta A, Settembre EC, Cirillo A, Pandit S, Ni YG, Hubbard B, Sitlani A, Carfí A.

EMBO Rep. 2011 Dec 1;12(12):1300-5. doi: 10.1038/embor.2011.205.

PubMed [citation]

PMID:: 22081141
PMCID:: PMC3245695

Cholesterol Levels in Genetically Determined Familial Hypercholesterolaemia in Russian Karelia.

Korneva VA, Kuznetsova TY, Bogoslovskaya TY, Polyakov DS, Vasilyev VB, Orlov AV, Mandelshtam MY.

Cholesterol. 2017;2017:9375818. doi: 10.1155/2017/9375818. Epub 2017 Mar 28.

PubMed [citation]

PMID:: 28458923
PMCID:: PMC5387824

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV004066478.2

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

Description

The c.1327T>C (p.W443R) alteration is located in exon 9 (coding exon 9) of the LDLR gene. This alteration results from a T to C substitution at nucleotide position 1327, causing the tryptophan (W) at amino acid position 443 to be replaced by an arginine (R). Based on data from gnomAD, the C allele has an overall frequency of 0.001% (1/251246) total alleles studied. The highest observed frequency was 0.001% (1/113560) of European (non-Finnish) alleles. This variant was identified in trans with a second LDLR variant in twins presenting with elevated LDL-C levels and multiple xanthomas (Zhang, 2022). It was also reported in conjunction with a gross deletion in an individual with elevated LDL-C levels and a history of myocardial infarction at age 21 years (Semenova, 2020). In addition, this variant has been identified alone in Russian individuals with elevated LDL-C levels (Korneva, 2017; Meshkov, 2021). This amino acid position is highly conserved in available vertebrate species. Internal structural analysis indicates that this variant, which impacts a conserved residue in the YWTD motif of an LDLR class B repeat, is structurally disruptive (Lo Surdo, 2011; 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 10, 2024

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