NM_000527.5(LDLR):c.826T>C (p.Cys276Arg) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 10, 2017
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:: RCV000781499.1

Allele description [Variation Report for NM_000527.5(LDLR):c.826T>C (p.Cys276Arg)]

NM_000527.5(LDLR):c.826T>C (p.Cys276Arg)

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.826T>C (p.Cys276Arg)

Other names:

FH Ceva

HGVS:

NC_000019.10:g.11107400T>C
NG_009060.1:g.23020T>C
NM_000527.5:c.826T>CMANE SELECT
NM_001195798.2:c.826T>C
NM_001195799.2:c.703T>C
NM_001195800.2:c.322T>C
NM_001195803.2:c.445T>C
NP_000518.1:p.Cys276Arg
NP_000518.1:p.Cys276Arg
NP_001182727.1:p.Cys276Arg
NP_001182728.1:p.Cys235Arg
NP_001182729.1:p.Cys108Arg
NP_001182732.1:p.Cys149Arg
LRG_274t1:c.826T>C
LRG_274:g.23020T>C
LRG_274p1:p.Cys276Arg
NC_000019.9:g.11218076T>C
NM_000527.4:c.826T>C
P01130:p.Cys276Arg
c.826T>C

Protein change:

C108R

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000715; UniProtKB: P01130#VAR_062375; dbSNP: rs879254692

NCBI 1000 Genomes Browser:

rs879254692

Molecular consequence:

NM_000527.5:c.826T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.826T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.703T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.322T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.445T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000919579	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Nov 10, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26036859, 23375686 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000919579

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Nov 10, 2017)

germline

clinical testing

PubMed (2)
[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

Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction.

Brænne I, Kleinecke M, Reiz B, Graf E, Strom T, Wieland T, Fischer M, Kessler T, Hengstenberg C, Meitinger T, Erdmann J, Schunkert H.

Eur J Hum Genet. 2016 Feb;24(2):191-7. doi: 10.1038/ejhg.2015.100. Epub 2015 Jun 3.

PubMed [citation]

PMID:: 26036859
PMCID:: PMC4717192

Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy.

Bertolini S, Pisciotta L, Rabacchi C, Cefalù AB, Noto D, Fasano T, Signori A, Fresa R, Averna M, Calandra S.

Atherosclerosis. 2013 Apr;227(2):342-8. doi: 10.1016/j.atherosclerosis.2013.01.007. Epub 2013 Jan 19.

PubMed [citation]

PMID:: 23375686

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919579.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: The LDLR c.826T>C (p.Cys276Arg) variant involves the alteration of a conserved nucleotide that results in the alteration of a cysteine residue at the protein level that is highly conserved across species (Bertolini 2013). The variant is located in the ligand-binding domain of the LDL receptor (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index), however these predictions have not been evaluated for functional impact by in vivo/vitro studies. This variant is absent in 246246 control chromosomes (gnomAD). The variant has been reported in individuals presented with hypercholesterolemia in heterozygous form (Bertolini 2003), however without providing clear evidence for causality. One clinical diagnostic laboratoy and a databases classified this variant as likely pathogenic, without evidence for independent evaluation. Variants involving the same codon such as C276G, C276F, C276W, and C276Y have been reported in affected individuals suggesting the functional importance of this codon. Taken together, this variant is classified as VUS-possibly pathogenic, until additional evidence becomes available.

#	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 29, 2024

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