dbSNP rs688: LDLR:p.Asn591Asn (chr19-11116926-C-T) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is The variant received -17 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_StrongBP7

The NM_000527.5(LDLR):c.1773C>T (p.Asn591Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.417 (AC=673,211) in the gnomAD database across 1,613,584 control chromosomes, including 147,093 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.446. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

Frequency

Genomes: 𝑓 0.34 ( 10427 hom., cov: 31)

Exomes 𝑓: 0.43 ( 136666 hom. )

Consequence

LDLR
NM_000527.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23

Conservation

PhyloP100: -4.22

Publications

206 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: SD, AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Natera
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.

Classification according to ACMG Germline Pathogenicity v2019

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 -17 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 2 star(s). ClinVar submissions strongly and reliably favor benignity (23/23 total B/LB).

BP7

Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.4456 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LDLR	NM_000527.5	MANE Select	c.1773C>T	p.Asn591Asn	synonymous	Exon 12 of 18	NP_000518.1	P01130-1
LDLR	NM_001195798.2		c.1773C>T	p.Asn591Asn	synonymous	Exon 12 of 18	NP_001182727.1	P01130-5
LDLR	NM_001195799.2		c.1650C>T	p.Asn550Asn	synonymous	Exon 11 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.1773C>T	p.Asn591Asn	synonymous	Exon 12 of 18	ENSP00000454071.1	P01130-1
LDLR	ENST00000252444.10	TSL:1	c.2031C>T	p.Asn677Asn	synonymous	Exon 12 of 18	ENSP00000252444.6	J3KMZ9
LDLR	ENST00000558013.5	TSL:1	c.1773C>T	p.Asn591Asn	synonymous	Exon 12 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes

AF:

0.337

AC:

51230

AN:

151818

Hom.:

10439

Cov.:

show subpopulations

Gnomad AFR

AF:

0.107

Gnomad AMI

AF:

0.349

Gnomad AMR

AF:

0.427

Gnomad ASJ

AF:

0.419

Gnomad EAS

AF:

0.173

Gnomad SAS

AF:

0.393

Gnomad FIN

AF:

0.493

Gnomad MID

AF:

0.434

Gnomad NFE

AF:

0.437

Gnomad OTH

AF:

0.362

GnomAD2 exomes

AF:

0.389

AC:

97866

AN:

251472

AF XY:

0.396

show subpopulations

Gnomad AFR exome

AF:

0.100

Gnomad AMR exome

AF:

0.415

Gnomad ASJ exome

AF:

0.432

Gnomad EAS exome

AF:

0.179

Gnomad FIN exome

AF:

0.483

Gnomad NFE exome

AF:

0.434

Gnomad OTH exome

AF:

0.409

GnomAD4 exome

AF:

0.426

AC:

622001

AN:

1461646

Hom.:

136666

Cov.:

AF XY:

0.425

AC XY:

309181

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.0953

AC:

3192

AN:

33478

American (AMR)

AF:

0.419

AC:

18718

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.435

AC:

11369

AN:

26136

East Asian (EAS)

AF:

0.148

AC:

5861

AN:

39700

South Asian (SAS)

AF:

0.393

AC:

33938

AN:

86252

European-Finnish (FIN)

AF:

0.472

AC:

25193

AN:

53410

Middle Eastern (MID)

AF:

0.448

AC:

2581

AN:

5758

European-Non Finnish (NFE)

AF:

0.447

AC:

496547

AN:

1111798

Other (OTH)

AF:

0.407

AC:

24602

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

21002

42004

63007

84009

105011

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14828

29656

44484

59312

74140

<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:

0.337

AC:

51210

AN:

151938

Hom.:

10427

Cov.:

AF XY:

0.341

AC XY:

25314

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.107

AC:

4420

AN:

41494

American (AMR)

AF:

0.426

AC:

6484

AN:

15216

Ashkenazi Jewish (ASJ)

AF:

0.419

AC:

1452

AN:

3468

East Asian (EAS)

AF:

0.172

AC:

890

AN:

5160

South Asian (SAS)

AF:

0.393

AC:

1894

AN:

4820

European-Finnish (FIN)

AF:

0.493

AC:

5197

AN:

10538

Middle Eastern (MID)

AF:

0.422

AC:

124

AN:

294

European-Non Finnish (NFE)

AF:

0.437

AC:

29676

AN:

67940

Other (OTH)

AF:

0.360

AC:

755

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1569

3139

4708

6278

7847

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

504

1008

1512

2016

2520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

TOPMed (Bravo)

AF:

0.321

AC:

84921

AN:

264690

Hom.:

16478

ALFA (dbGaP/dbSNP Allele Frequency Aggregator)

AF:

0.400

AC:

182117

AN:

455066

Hom.:

38700

Local populations

ABraOM SABE-WGS-1171

AF:

0.355

AC:

832

AN:

2342

Hom.:

162

ChinaMAP Phase 1

AF:

0.167

Denmark Genome

AF:

0.420

AC:

126

AN:

300

ESP6500 (Exome Variant Server)

AF:

0.335

AC:

4360

AN:

13006

show subpopulations

European American

AF:

0.450

AC:

3874

AN:

8600

African American

AF:

0.110

AC:

486

AN:

4406

GenomeAsia100K

AF:

0.266

AC:

923

AN:

3478

show subpopulations

Oceania

AF:

0.446

AC:

AN:

148

Hom.:

North-East Asia

AF:

0.171

AC:

120

AN:

702

Hom.:

South-East Asia

AF:

0.257

AC:

178

AN:

692

Hom.:

South Asia

AF:

0.297

AC:

430

AN:

1448

Hom.:

Africa

AF:

0.0481

AC:

AN:

208

Hom.:

America

AF:

0.288

AC:

AN:

Hom.:

West Eurasia

AF:

0.456

AC:

104

AN:

228

Hom.:

Korea4K (4,157 Koreans)

AF:

0.144

AC:

1040

AN:

7232

Qatari Genome

AF:

0.481

AC:

965

AN:

2008

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.121

AC:

14833

AN:

122156

Hom.:

951

Turkish Variome

AF:

0.407

AC:

2735

AN:

6718

Hom.:

591

UK10K

AF:

0.449

AC:

3392

AN:

7562

show subpopulations

TwinsUK

AF:

0.444

AC:

1588

AN:

3574

ALSPAC

AF:

0.452

AC:

1743

AN:

3854

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.170

AC:

1524

AN:

8960

Hom.:

133

Case/control cohorts

Cohort

Cases

Controls

ASC

(Autism)

4592 / 11098AF: 0.413768

7244 / 17604AF: 0.411497

BipEx

(Bipolar disorder (including schizoaffective))

12447 / 28420AF: 0.437966

12635 / 28844AF: 0.438046

Epi25

(Epilepsy)

16330 / 41956AF: 0.389217

27121 / 66882AF: 0.405505

SCHEMA

(Schizophrenia)

41202 / 131958AF: 0.312236

69948 / 212874AF: 0.328589

Allele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypercholesterolemia, familial, 1 (9)

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

-0.74

CADD

Benign

0.092

(source)

DANN

Benign

0.70

PhyloP100

-4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

AlphaGenome AVI

Benign

0.00076

(source)

GPN-Star LLR

-0.71

(source)

GPN-Star score

0.45

(source)

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

Pangolin (max)

Benign

0.0

(source)

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

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

Case/control cohorts

ClinVar

Computational scores

Splicing

Publications

Other links and lift over