dbSNP rs5927: LDLR:p.Arg744Arg (chr19-11123265-A-G) – ACMG Classification: Benign (-21 pts)

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.2232A>G(p.Arg744Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.76 in 1,613,474 control chromosomes in the GnomAD database, including 467,950 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene LDLR is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.75 ( 43048 hom., cov: 31)

Exomes 𝑓: 0.76 ( 424902 hom. )

Consequence

LDLR
NM_000527.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:21

Conservation

PhyloP100: -0.822

Publications

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

LDLR links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000527.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Specifications for LDLR are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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 19-11123265-A-G is Benign according to our data. Variant chr19-11123265-A-G is described in ClinVar as Benign. ClinVar VariationId is 252262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.822 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LDLR	NM_000527.5	MANE Select	c.2232A>G	p.Arg744Arg	synonymous	Exon 15 of 18	NP_000518.1	P01130-1
LDLR	NM_001195798.2		c.2232A>G	p.Arg744Arg	synonymous	Exon 15 of 18	NP_001182727.1	P01130-5
LDLR	NM_001195799.2		c.2109A>G	p.Arg703Arg	synonymous	Exon 14 of 17	NP_001182728.1	P01130-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LDLR	ENST00000558518.6	TSL:1 MANE Select	c.2232A>G	p.Arg744Arg	synonymous	Exon 15 of 18	ENSP00000454071.1	P01130-1
LDLR	ENST00000252444.10	TSL:1	c.2490A>G	p.Arg830Arg	synonymous	Exon 15 of 18	ENSP00000252444.6	J3KMZ9
LDLR	ENST00000558013.5	TSL:1	c.2232A>G	p.Arg744Arg	synonymous	Exon 15 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes

AF:

0.751

AC:

113999

AN:

151864

Hom.:

43015

Cov.:

show subpopulations

Gnomad AFR

AF:

0.691

Gnomad AMI

AF:

0.676

Gnomad AMR

AF:

0.834

Gnomad ASJ

AF:

0.714

Gnomad EAS

AF:

0.949

Gnomad SAS

AF:

0.777

Gnomad FIN

AF:

0.769

Gnomad MID

AF:

0.747

Gnomad NFE

AF:

0.751

Gnomad OTH

AF:

0.756

GnomAD2 exomes

AF:

0.781

AC:

196302

AN:

251300

AF XY:

0.775

show subpopulations

Gnomad AFR exome

AF:

0.685

Gnomad AMR exome

AF:

0.881

Gnomad ASJ exome

AF:

0.735

Gnomad EAS exome

AF:

0.948

Gnomad FIN exome

AF:

0.768

Gnomad NFE exome

AF:

0.753

Gnomad OTH exome

AF:

0.773

GnomAD4 exome

AF:

0.761

AC:

1112203

AN:

1461492

Hom.:

424902

Cov.:

AF XY:

0.760

AC XY:

552356

AN XY:

727064

show subpopulations

African (AFR)

AF:

0.679

AC:

22725

AN:

33476

American (AMR)

AF:

0.876

AC:

39168

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.732

AC:

19127

AN:

26134

East Asian (EAS)

AF:

0.948

AC:

37643

AN:

39700

South Asian (SAS)

AF:

0.754

AC:

64997

AN:

86252

European-Finnish (FIN)

AF:

0.767

AC:

40932

AN:

53366

Middle Eastern (MID)

AF:

0.724

AC:

4177

AN:

5766

European-Non Finnish (NFE)

AF:

0.753

AC:

837654

AN:

1111696

Other (OTH)

AF:

0.758

AC:

45780

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

15064

30128

45191

60255

75319

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20368

40736

61104

81472

101840

<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:

0.751

AC:

114090

AN:

151982

Hom.:

43048

Cov.:

AF XY:

0.755

AC XY:

56110

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.691

AC:

28652

AN:

41446

American (AMR)

AF:

0.834

AC:

12716

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.714

AC:

2475

AN:

3466

East Asian (EAS)

AF:

0.949

AC:

4900

AN:

5164

South Asian (SAS)

AF:

0.776

AC:

3737

AN:

4816

European-Finnish (FIN)

AF:

0.769

AC:

8124

AN:

10570

Middle Eastern (MID)

AF:

0.745

AC:

219

AN:

294

European-Non Finnish (NFE)

AF:

0.751

AC:

51060

AN:

67954

Other (OTH)

AF:

0.754

AC:

1593

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

1478

2956

4433

5911

7389

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

856

1712

2568

3424

4280

<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:

0.750

Hom.:

75530

Bravo

AF:

0.754

Asia WGS

AF:

0.818

AC:

2844

AN:

3478

EpiCase

AF:

0.741

EpiControl

AF:

0.744

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypercholesterolemia, familial, 1 (7)

not specified (7)

Familial hypercholesterolemia (4)

not provided (2)

Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

1.4

(source)

DANN

Benign

0.37

PhyloP100

-0.82

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over