rs5929

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000527.5(LDLR):c.1617C>T(p.Pro539Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0551 in 1,612,458 control chromosomes in the GnomAD database, including 4,226 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.073 ( 617 hom., cov: 32)

Exomes 𝑓: 0.053 ( 3609 hom. )

Consequence

LDLR
NM_000527.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: -3.35

Publications

38 publications found

Variant links:

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

LDLR Gene-Disease associations (from GenCC):

hypercholesterolemia, familial, 1
Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
homozygous familial hypercholesterolemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LDLR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 19-11116124-C-T is Benign according to our data. Variant chr19-11116124-C-T is described in ClinVar as Benign. ClinVar VariationId is 251936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.35 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.271 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5 link	c.1617C>T	p.Pro539Pro	synonymous_variant	Exon 11 of 18	ENST00000558518.6	NP_000518.1	P01130-1A0A024R7D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6 link	c.1617C>T	p.Pro539Pro	synonymous_variant	Exon 11 of 18	1	NM_000527.5	ENSP00000454071.1		P01130-1

Frequencies

GnomAD3 genomes

AF:

0.0726

AC:

11031

AN:

152010

Hom.:

614

Cov.:

show subpopulations

Gnomad AFR

AF:

0.110

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0565

Gnomad ASJ

AF:

0.0637

Gnomad EAS

AF:

0.283

Gnomad SAS

AF:

0.0848

Gnomad FIN

AF:

0.0524

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.0404

Gnomad OTH

AF:

0.0755

GnomAD2 exomes

AF:

0.0756

AC:

19015

AN:

251466

AF XY:

0.0735

show subpopulations

Gnomad AFR exome

AF:

0.117

Gnomad AMR exome

AF:

0.0760

Gnomad ASJ exome

AF:

0.0667

Gnomad EAS exome

AF:

0.271

Gnomad FIN exome

AF:

0.0533

Gnomad NFE exome

AF:

0.0425

Gnomad OTH exome

AF:

0.0673

GnomAD4 exome

AF:

0.0532

AC:

77739

AN:

1460330

Hom.:

3609

Cov.:

AF XY:

0.0536

AC XY:

38940

AN XY:

726536

show subpopulations

African (AFR)

AF:

0.116

AC:

3881

AN:

33408

American (AMR)

AF:

0.0738

AC:

3298

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0634

AC:

1657

AN:

26120

East Asian (EAS)

AF:

0.298

AC:

11820

AN:

39668

South Asian (SAS)

AF:

0.0801

AC:

6903

AN:

86202

European-Finnish (FIN)

AF:

0.0541

AC:

2890

AN:

53374

Middle Eastern (MID)

AF:

0.0550

AC:

317

AN:

5764

European-Non Finnish (NFE)

AF:

0.0392

AC:

43506

AN:

1110736

Other (OTH)

AF:

0.0575

AC:

3467

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

3435

6869

10304

13738

17173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1840

3680

5520

7360

9200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0726

AC:

11048

AN:

152128

Hom.:

617

Cov.:

AF XY:

0.0746

AC XY:

5546

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.110

AC:

4580

AN:

41504

American (AMR)

AF:

0.0566

AC:

864

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.0637

AC:

221

AN:

3468

East Asian (EAS)

AF:

0.283

AC:

1460

AN:

5156

South Asian (SAS)

AF:

0.0853

AC:

411

AN:

4820

European-Finnish (FIN)

AF:

0.0524

AC:

556

AN:

10606

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0404

AC:

2748

AN:

68002

Other (OTH)

AF:

0.0771

AC:

163

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

503

1005

1508

2010

2513

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

240

360

480

600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0573

Hom.:

330

Bravo

AF:

0.0757

Asia WGS

AF:

0.154

AC:

535

AN:

3478

EpiCase

AF:

0.0436

EpiControl

AF:

0.0404

ClinVar

Significance: Benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Benign:8

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:research

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:literature only

- -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

8/95 non-FH individuals; MAF = 4,7% in 86 Spanish healthy individuals -

Jul 30, 2018

Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Due to the increased occurrence of the mutation (>= 5%), this variant is classified as benign. -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jun 22, 2017

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:4

Oct 21, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial hypercholesterolemia

Benign:3

Feb 09, 2023

Cohesion Phenomics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2022

GENinCode PLC

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 06, 2016

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: This LDLR c.1617C>T variant affects a non-conserved nucleotide, resulting in synonymous amino acid change. 5/5 splice-site tools via Alamut predict that this variant does not affect normal splicing. This variant was found in 9229/121288 control chromosomes from the large and broad populations of ExAC at a frequency of 0.0760916 including several homozygotes, which is over 60 times greater than the maximal expected frequency of a pathogenic LDLR allele (0.0012508), suggesting this variant is benign. The variant has also been reported to co-occur with other potentially pathogenic variants such as c.68-1G>A (internal finding in one specimen), c.1634G>A (internal finding in one specimen), and p. p.Cys667Ser (Zakharova_2005), further supporting the benign outcome. Additionally, the variant is reported in the literature to be a common polymorphism that has no effect on plasma triglyceride, HDL cholesterol, apoA1 or lipoprotein (a) levels (Wu_Atheroscl_1999). Taken together, this variant has been classified as Benign. -

Smith-Lemli-Opitz syndrome

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 16, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.19

(source)

DANN

Benign

0.45

PhyloP100

-3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over