rs72658860

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PP3PP1BS2BA1BP2

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.970G>A (p.Gly324Ser) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BA1, BS2, BP2, PP1 and PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BA1 - FAF = 0.01153 (1.153%) in African/African American exomes (gnomAD v2.1.1). BS2 - Identified in 4 heterozygous non-affected family members from different labs.BP2 - variant identified 1 index case with heterozygous FH phenotype who is double heterozygous with NM_000384.3(APOB):c.10580G>A p.Arg3527Gln (ClinVar ID 17890) - classified as Pathogenic by the general ACMG guidelines (Chora et al., 2018).PP1 - variant segregates with phenotype in 2 informative meiosis in 1 family from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.PP3 - REVEL = 0.815.Variant has 1 stand alone, 1 Strong and 1 Supporting evidence codes towards Benign, enough to classify as Benign, and only 2 Supporting codes towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Benign. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023801/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.0038 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 3 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

5

7

5

Clinical Significance

Benign reviewed by expert panel P:2U:3B:18O:1

Conservation

PhyloP100: 6.61

Publications

13 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 -11 ACMG points.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

BP2

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.970G>A	p.Gly324Ser	missense	Exon 7 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.970G>A	p.Gly324Ser	missense	Exon 7 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.847G>A	p.Gly283Ser	missense	Exon 6 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.970G>A	p.Gly324Ser	missense	Exon 7 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.1228G>A	p.Gly410Ser	missense	Exon 7 of 18	ENSP00000252444.6
	LDLR	ENST00000558013.5	TSL:1	c.970G>A	p.Gly324Ser	missense	Exon 7 of 18	ENSP00000453346.1

Frequencies

GnomAD3 genomes

AF:

0.00376

AC:

572

AN:

152124

Hom.:

5

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.0133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000919

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000881

AC:

221

AN:

250886

AF XY:

0.000619

show subpopulations

Gnomad AFR exome

AF:

0.0130

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000343

AC:

502

AN:

1461590

Hom.:

3

Cov.:

31

AF XY:

0.000276

AC XY:

201

AN XY:

727096

show subpopulations

African (AFR)

AF:

0.0132

AC:

442

AN:

33476

American (AMR)

AF:

0.000358

AC:

16

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

0

AN:

39694

South Asian (SAS)

AF:

0.0000116

AC:

1

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

53190

Middle Eastern (MID)

AF:

0.000173

AC:

1

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

4

AN:

1111958

Other (OTH)

AF:

0.000629

AC:

38

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0

28

56

83

111

139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

0

20

40

60

80

100

<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:

0.00376

AC:

572

AN:

152242

Hom.:

5

Cov.:

32

AF XY:

0.00353

AC XY:

263

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0133

AC:

553

AN:

41550

American (AMR)

AF:

0.000918

AC:

14

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

0

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

1

AN:

68018

Other (OTH)

AF:

0.00189

AC:

4

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0

26

53

79

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

0

10

20

30

40

50

<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:

0.00139

Hom.:

4

Bravo

AF:

0.00407

ESP6500AA

AF:

0.0141

AC:

62

ESP6500EA

AF:

0.00

AC:

0

ExAC

AF:

0.00115

AC:

140

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

2

3

5

Hypercholesterolemia, familial, 1 (10)

-

-

4

Familial hypercholesterolemia (4)

-

-

4

not provided (5)

-

-

3

not specified (3)

-

-

1

Cardiovascular phenotype (1)

-

-

1

Hypercholesterolemia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.083

T

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

25

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Uncertain

0.96

D

MetaRNN

Benign

0.031

T

MetaSVM

Pathogenic

0.91

D

MutationAssessor

Uncertain

2.8

M

PhyloP100

6.6

PrimateAI

Benign

0.36

T

PROVEAN

Pathogenic

-5.8

D

REVEL

Pathogenic

0.81

Sift

Benign

0.041

D

Sift4G

Uncertain

0.036

D

Polyphen

1.0

D

Vest4

0.55

MVP

1.0

MPC

0.31

ClinPred

0.15

T

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.63

gMVP

0.90

Mutation Taster

=12/88

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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Other links and lift over

dbSNP: rs72658860; hg19: chr19-11221357; API