GeneBe

rs144172724

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS4PP1_StrongPM3PM2PP3PP4PS3_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.301G>A (p.Glu101Lys) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_Strong, PS4, PM2, PM3, PS3_Moderate, PP3 and PP4) 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: PP1_strong - variant segregates with the FH phenotype in at least 19 relatives with the variant and LDL-C above the 75th percentile from several labs (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, Ambry, Robarts Research Institute), so PP1_Strong is met.PS4 - variant meets PM2 and is identified in at least 16 index cases who fulfill validated clinical criteria for FH from several labs (SB criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge and DLCN >=6 from Color, Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) and Robarts Research Institute), so PS4 is met.PM2 - PopMax MAF = 0.00003266 (0.003%) in south asian exomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met.PM3 - variant meets PM2 and was identified in 1 index case with LDL 16.2 mmol/L and also LDLR exon 15 deletion from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) - Likely pathogenic by these guidelines, so PM3 is metPS3_moderate - Level 2 FS: Hobbs et al., 1992 (PMID 1301956): Hmz patient fibroblast, 125I-LDL assays - results: 15-30% LDLR activity. Activity is below 70% of wild-type, so PS3_Moderate is met.PP3 - REVEL = 0.896. It is above 0.75, so PP3 is met.PP4 - variant meets PM2 and is identified in at least 1 index case who fulfills SB criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. so, PP4 is met LINK:https://erepo.genome.network/evrepo/ui/classification/CA023687/MONDO:0007750/013

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

LDLR
NM_000527.5 missense

Scores

12
6
1

Clinical Significance

Pathogenic reviewed by expert panel P:31O:1

Conservation

PhyloP100: 8.06

Publications

28 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

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

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PS3
For more information check the summary or visit ClinGen Evidence Repository.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM3
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP3
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

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
LDLR
NM_000527.5
MANE Select
c.301G>Ap.Glu101Lys
missense
Exon 3 of 18NP_000518.1P01130-1
LDLR
NM_001195798.2
c.301G>Ap.Glu101Lys
missense
Exon 3 of 18NP_001182727.1P01130-5
LDLR
NM_001195800.2
c.301G>Ap.Glu101Lys
missense
Exon 3 of 16NP_001182729.1P01130-3

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
LDLR
ENST00000558518.6
TSL:1 MANE Select
c.301G>Ap.Glu101Lys
missense
Exon 3 of 18ENSP00000454071.1P01130-1
LDLR
ENST00000252444.10
TSL:1
c.559G>Ap.Glu187Lys
missense
Exon 3 of 18ENSP00000252444.6J3KMZ9
LDLR
ENST00000558013.5
TSL:1
c.301G>Ap.Glu101Lys
missense
Exon 3 of 18ENSP00000453346.1P01130-5

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152180
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000159
AC:
4
AN:
251462
AF XY:
0.0000294
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:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000294
AC:
43
AN:
1461310
Hom.:
0
Cov.:
31
AF XY:
0.0000220
AC XY:
16
AN XY:
726946
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33468
American (AMR)
AF:
0.00
AC:
0
AN:
44708
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26114
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39666
South Asian (SAS)
AF:
0.0000232
AC:
2
AN:
86222
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53362
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5754
European-Non Finnish (NFE)
AF:
0.0000369
AC:
41
AN:
1111656
Other (OTH)
AF:
0.00
AC:
0
AN:
60360
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.480
Heterozygous variant carriers
0
3
6
9
12
15
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000197
AC:
3
AN:
152180
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74336
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41452
American (AMR)
AF:
0.00
AC:
0
AN:
15256
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5192
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10614
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68044
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000892
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

ClinVar submissions
Significance:Pathogenic
Revision:reviewed by expert panel
View on ClinVar
Pathogenic
VUS
Benign
Condition
16
-
-
Hypercholesterolemia, familial, 1 (16)
6
-
-
Familial hypercholesterolemia (6)
5
-
-
not provided (6)
1
-
-
Cardiovascular phenotype (1)
1
-
-
Dyslipidemia (1)
1
-
-
Homozygous familial hypercholesterolemia (1)
1
-
-
Hypercholesterolemia (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.96
D
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.95
D
M_CAP
Pathogenic
0.89
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.7
H
PhyloP100
8.1
PrimateAI
Benign
0.45
T
PROVEAN
Uncertain
-3.6
D
REVEL
Pathogenic
0.90
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.012
D
Varity_R
0.98
gMVP
1.0
Mutation Taster
=0/100
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs144172724;
hg19: chr19-11213450;
COSMIC: COSV52945517;
COSMIC: COSV52945517;
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