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

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Nov 2, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000590088.13

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:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000697254	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 6, 2017)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25463123, 26361156, 23375686, 1301956 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000752422	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 29, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 1301956, 11317361, 11462246, 15015036, 23130880, 27765764, 28492532
SCV001358587	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 2, 2023)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 1301956, 11462246, 11810272, 15015036, 17347910, 23130880, 27578104, 27765764, 28965616, 32829317, 33454241, 33794673, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000697254

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Apr 6, 2017)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000752422

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 29, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV001358587

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 2, 2023)

germline

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

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

Familial Hypercholesterolemia in Greek children and their families: genotype-to-phenotype correlations and a reconsideration of LDLR mutation spectrum.

Mollaki V, Progias P, Drogari E.

Atherosclerosis. 2014 Dec;237(2):798-804. doi: 10.1016/j.atherosclerosis.2014.09.031. Epub 2014 Oct 30.

PubMed [citation]

PMID:: 25463123

Universal Screening for Familial Hypercholesterolemia in Children.

Klančar G, Grošelj U, Kovač J, Bratanič N, Bratina N, Trebušak Podkrajšek K, Battelino T.

J Am Coll Cardiol. 2015 Sep 15;66(11):1250-1257. doi: 10.1016/j.jacc.2015.07.017.

PubMed [citation]

PMID:: 26361156

See all PubMed Citations (18)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697254.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: The LDLR c.858C>A (p.Ser286Arg) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index), which was confirmed by low LDLR activity in patient carrying this variant (Hobbs_1992). This variant was found in 3/121368 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant has been reported in a large number of FH patients with milder phenotype. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Taken together, this variant 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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000752422.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 286 of the LDLR protein (p.Ser286Arg). This variant is present in population databases (rs140241383, gnomAD 0.007%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 11317361, 11462246, 15015036, 23130880, 27765764). This variant is also known as p.Ser265Arg. ClinVar contains an entry for this variant (Variation ID: 251488). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. For these reasons, this variant has been 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

From Color Diagnostics, LLC DBA Color Health, SCV001358587.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

This missense variant replaces serine with arginine at codon 286 in the LDLR type A repeat 7 of the ligand binding domain of the LDLR protein. This variant is also known as p.Ser265Arg in the mature protein and as FH Greece-2 in the literature. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental functional study has shown that this variant in compound heterozygosity with p.Cys173Arg reduces LDLR activity to 5-15% compared to wild type (PMID: 1301956). This variant has been reported in over 150 individuals affected with familial hypercholesterolemia (PMID: 11462246, 11810272, 15015036, 17347910, 23130880, 27578104, 27765764, 28965616, 32829317, 33454241, 33794673; Color Health internal data) and is a recurrent mutation in the Greek population (PMID: 27578104). This variant has been identified in 7/251430 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant 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: Oct 20, 2024

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