NM_000527.5(LDLR):c.28T>C (p.Trp10Arg) AND Cardiovascular phenotype

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Apr 30, 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:: RCV002436068.2

Allele description [Variation Report for NM_000527.5(LDLR):c.28T>C (p.Trp10Arg)]

NM_000527.5(LDLR):c.28T>C (p.Trp10Arg)

Genes:

LDLR-AS1:LDLR antisense RNA 1 [Gene - HGNC]
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.28T>C (p.Trp10Arg)

HGVS:

NC_000019.10:g.11089576T>C
NG_009060.1:g.5196T>C
NM_000527.5:c.28T>CMANE SELECT
NM_001195798.2:c.28T>C
NM_001195799.2:c.28T>C
NM_001195800.2:c.28T>C
NM_001195803.2:c.28T>C
NP_000518.1:p.Trp10Arg
NP_000518.1:p.Trp10Arg
NP_001182727.1:p.Trp10Arg
NP_001182728.1:p.Trp10Arg
NP_001182729.1:p.Trp10Arg
NP_001182732.1:p.Trp10Arg
LRG_274t1:c.28T>C
LRG_274:g.5196T>C
LRG_274p1:p.Trp10Arg
NC_000019.9:g.11200252T>C
NM_000527.4:c.28T>C
NR_163945.1:n.84A>G
c.28T>C

Protein change:

W10R

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000260;

Molecular consequence:

NM_000527.5:c.28T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.28T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.28T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.28T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.28T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_163945.1:n.84A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV002751844	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Apr 30, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16250003, 25461735, 29874871 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002751844

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Apr 30, 2019)

germline

clinical testing

PubMed (3)
[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

Update of the molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Kastelein JJ, Defesche JC.

Hum Mutat. 2005 Dec;26(6):550-6.

PubMed [citation]

PMID:: 16250003

Familial hypercholesterolemia in Brazil: cascade screening program, clinical and genetic aspects.

Jannes CE, Santos RD, de Souza Silva PR, Turolla L, Gagliardi AC, Marsiglia JD, Chacra AP, Miname MH, Rocha VZ, Filho WS, Krieger JE, Pereira AC.

Atherosclerosis. 2015 Jan;238(1):101-7. doi: 10.1016/j.atherosclerosis.2014.11.009. Epub 2014 Nov 14.

PubMed [citation]

PMID:: 25461735

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV002751844.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.W10R variant (also known as c.28T>C), located in coding exon 1 of the LDLR gene, results from a T to C substitution at nucleotide position 28. The tryptophan at codon 10 is replaced by arginine, an amino acid with dissimilar properties. This variant has been described in familial hypercholesterolemia (FH) cohorts, although clinical details were limited (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7). An alternate nucleotide change at this position, p.W10R c.28T>A, was reported to be de novo in a pediatric FH case, and functional activity in skin fibroblasts showed reduced LDLR activity (Cassanelli S et al. Clin. Genet., 1998 May;53:391-5). This amino acid position is well conserved in available 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: Feb 25, 2025

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