rs138315511

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS4_ModeratePM2PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1085A>C (p.Asp362Ala) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4 and PS4_Moderate) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).The supporting evidence is as follows:PM2 - PopMax MAF = 0.0001782 (0.01782%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1).PS4_Moderate - Variant meets PM2 and is identified in 8 unrelated index cases (5 cases with Simon-Broome criteria of definite/possible FH published in PMID:16542394, Denmark; at least 1 case with DLCN≥6 published in PMID:11810272, Netherlands; 1 case with DLCN criteria ≥6 from Robarts Research Institute, Canada; 1 case with Simon-Broome criteria of possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czechia.PP4 - Variant meets PM2 and is identified in at least one case who fufills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023415/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:3U:12B:2

Conservation

PhyloP100: 2.65

Publications

6 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, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, 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: Uncertain_significance. The variant received 5 ACMG points.

PS4

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

PM2

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

PP4

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LDLR	NM_000527.5	MANE Select	c.1085A>C	p.Asp362Ala	missense	Exon 8 of 18	NP_000518.1	P01130-1
LDLR	NM_001195798.2		c.1085A>C	p.Asp362Ala	missense	Exon 8 of 18	NP_001182727.1	P01130-5
LDLR	NM_001195799.2		c.962A>C	p.Asp321Ala	missense	Exon 7 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.1085A>C	p.Asp362Ala	missense	Exon 8 of 18	ENSP00000454071.1	P01130-1
LDLR	ENST00000252444.10	TSL:1	c.1343A>C	p.Asp448Ala	missense	Exon 8 of 18	ENSP00000252444.6	J3KMZ9
LDLR	ENST00000558013.5	TSL:1	c.1085A>C	p.Asp362Ala	missense	Exon 8 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000875

AC:

AN:

251334

AF XY:

0.0000810

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000157

AC:

229

AN:

1461506

Hom.:

Cov.:

AF XY:

0.000157

AC XY:

114

AN XY:

727068

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000563

AC:

AN:

53254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000192

AC:

214

AN:

1111842

Other (OTH)

AF:

0.000166

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0000723

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000124

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypercholesterolemia, familial, 1 (8)

Familial hypercholesterolemia (4)

Cardiovascular phenotype (1)

Dyslipidemia (1)

Hypercholesterolemia (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.074

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

Eigen

Benign

-0.061

Eigen_PC

Benign

-0.13

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.67

M_CAP

Pathogenic

0.41

MetaRNN

Uncertain

0.64

MetaSVM

Uncertain

0.35

MutationAssessor

Benign

0.74

PhyloP100

2.6

PrimateAI

Benign

0.31

PROVEAN

Pathogenic

-5.4

REVEL

Pathogenic

0.70

Sift

Uncertain

0.023

Sift4G

Uncertain

0.050

Polyphen

0.95

Vest4

0.39

MVP

1.0

MPC

0.33

ClinPred

0.35

GERP RS

3.3

Varity_R

0.22

gMVP

0.97

Mutation Taster

=41/59

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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