NM_000527.5(LDLR):c.858C>A (p.Ser286Arg) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 3, 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:: RCV002446473.5

Allele description [Variation Report for NM_000527.5(LDLR):c.858C>A (p.Ser286Arg)]

NM_000527.5(LDLR):c.858C>A (p.Ser286Arg)

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.858C>A (p.Ser286Arg)

Other names:

NP_000518.1:p.S286R; NM_000527.5(LDLR):c.858C>A

HGVS:

NC_000019.10:g.11107432C>A
NG_009060.1:g.23052C>A
NM_000527.5:c.858C>AMANE SELECT
NM_001195798.2:c.858C>A
NM_001195799.2:c.735C>A
NM_001195800.2:c.354C>A
NM_001195803.2:c.477C>A
NP_000518.1:p.Ser286Arg
NP_000518.1:p.Ser286Arg
NP_001182727.1:p.Ser286Arg
NP_001182728.1:p.Ser245Arg
NP_001182729.1:p.Ser118Arg
NP_001182732.1:p.Ser159Arg
LRG_274t1:c.858C>A
LRG_274:g.23052C>A
LRG_274p1:p.Ser286Arg
NC_000019.9:g.11218108C>A
NM_000527.4:c.858C>A
P01130:p.Ser286Arg
c.858C>A

Protein change:

S118R

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000129; UniProtKB: P01130#VAR_005351; dbSNP: rs140241383

NCBI 1000 Genomes Browser:

rs140241383

Molecular consequence:

NM_000527.5:c.858C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.858C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.735C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.354C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.477C>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
SCV002681307	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (May 3, 2023)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 11462246, 1301956, 15015036, 15200491, 19837725, 22390909, 23130880, 23375686, 25463123, 26361156, 27578104, 27765764, 28965616, 9090532, 9259195, 9544850 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002681307

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(May 3, 2023)

germline

clinical testing

PubMed (16)
[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

Identification of recurrent and novel mutations in the LDL receptor gene in German patients with familial hypercholesterolemia.

Nauck MS, Köster W, Dörfer K, Eckes J, Scharnagl H, Gierens H, Nissen H, Nauck MA, Wieland H, März W.

Hum Mutat. 2001 Aug;18(2):165-6.

PubMed [citation]

PMID:: 11462246

Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.

Hobbs HH, Brown MS, Goldstein JL.

Hum Mutat. 1992;1(6):445-66. Review.

PubMed [citation]

PMID:: 1301956

See all PubMed Citations (16)

Details of each submission

From Ambry Genetics, SCV002681307.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

The p.S286R pathogenic mutation (also known as c.858C>A), located in coding exon 6 of the LDLR gene, results from a C to A substitution at nucleotide position 858. The serine at codon 286 is replaced by arginine, an amino acid with dissimilar properties, and is located in the ligand binding 7 domain. This alteration, also referred to as S265R and FH Greece-2, has been detected in several cohorts and multiple unrelated individuals with hypercholesterolemia from various ethnic backgrounds, and has been reported to result in reduced LDL receptor activity (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Day IN et al. Hum. Mutat., 1997;10:116-27; Traeger-Synodinos J et al. Hum. Genet., 1998 Mar;102:343-7; Nauck MS et al. Hum. Mutat., 2001 Aug;18:165-6; Mihaylov VA et al. J. Hum. Genet., 2004 Mar;49:173-6; Whittall RA et al. Ann. Clin. Biochem., 2010 Jan;47:44-55; Huijgen R et al. Eur. Heart J., 2012 Sep;33:2325-30; Mollaki V et al. Atherosclerosis, 2014 Dec;237:798-804; Klanar G et al. J. Am. Coll. Cardiol., 2015 Sep;66:1250-1257). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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: Oct 8, 2024

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